Naphthyloxyacetic acid derivatives and drugs comprising the same as active ingredients

ABSTRACT

The naphthyloxyacetic acid derivatives of the formula (I) ##STR1## wherein A is H, --(alkylene)COOR 1 , --(alkylene)CONR 2  R.sup., --(alkylene)OH, --(alkylene)tetrazole, --(alkylene)CN; E is single bond or alkylene; G is --S--, --SO--, --SO 2  --, --O-- or --NR 4  --; L is alkylene, --(CH 2 ) m  --CH=CH--(CH 2 ) n  -- or --(CH 2 ) x  --CH(OH)--(CH 2 ) y  --; M is phenyl, phenyl(thio, oxy, amino), diphenylmethyl, diphenylmethyl(thio, oxy, amino), and pharmaceutical composition comprising them as an active ingradient. The compounds of the formula (I) can combine PGE 2  receptor and exhibit the activity to antagonize or agonize for PGE 2  receptor. Therefore, they are useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, as antidiarrheals, sleep inducer, diuretic, anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis or antihypertensive etc.

This application is the national phase of PCT/JP96/01833, Jul. 2, 1996,now WO97/05091.

FIELD OF TECHNOLOGY

This invention is related to the naphthyloxyacetic acid derivatives.More particularly, this invention is related to

(1) the naphthyloxyacetic acid derivatives of the formula (I) ##STR2##wherein all symbols are the same meaning as hereafter defined, ornon-toxic salts thereof, acid addition salts thereof or their hydratesand

(2) a pharmaceutical composition (Prostaglandin E₂ (PGE₂) antagonists oragonists) which comprises them as an active ingredient.

BACKGROUND

PGE₂ has been known as metabolite in the arachidonate cascade. Inaddition, the recent progress in the molecule biological technologymakes the existence of three PGE₂ receptors clear as shown in thefollowing and have been making the relationship between each receptorand appearance of biological activity clear. For example, EP, receptormay cause contraction of the smooth muscle of digestive canal orbronchus etc. and promote the release of neurotransmitter. Therepresentative activity of EP₂ receptor is relaxation of smooth muscleof bronchus or ileum etc. or vasodilatation and reduce of the bloodpressure due to relaxation of vascular smooth muscle. As the activity ofEP₃ receptor, uterine muscle contraction, suppression of gastric acidsecretion, inhibition of reabsorption of water and ion by vasopressin inrenes, inhibition of fat decomposition in fat tissue, inhibition ofrelease of neurotransmitter and glucose-decomposition by gulcagon inliver cell etc. have been known. In addition, recently, the existence offourth receptor is suggested. (Biochemistry Vol. 66, No. 3, pp. 218-231(1994))

Therefor, to antagonize PGE₂ receptor means to suppress the effectsabove mentioned, so such an activity is linked to inhibit diuretic, toinhibit hyperlipemia, to inhibit reduce of blood sugar, to inhibituterine contraction, to have analgesic action, to inhibit digestiveperistalsis, to induce sleep. Therefor, PGE₂ receptor antagonists areconsidered to be useful as anti-hyperlipemia, for the prevention ofabortion, for analgesics, or as antidiarrheals or sleep inducer.

To agonize for PGE₂ receptor means to promote the effects abovementioned, so such an activity is linked to have diuretic, to promotehyperlipemia, to promote reduce of blood sugar, to contractile uterine,to promote digestive peristalsis, to suppress gastric acid secretion orto reduce blood pressure. Therefor, PGE₂ receptor agonists areconsidered to be useful for diuretic, anti-diabetes, abortient,cathartics, antiulcer, anti-gastritis or antihypertensive.

In such a background, a lot of compounds which agonize or antagonize forPGE₂ receptors have been proposed.

For example, in the specification of EP-0657422, it is disclosed thatthe compounds of the formula (A) ##STR3## wherein R^(1A) is --COOR⁴ A inwhich R^(4A) is hydrogen or C1-4 alkyl, --CONR^(5A) R^(8A) in whichR^(5A) and R^(6A) each, independently, is hydrogen, C1-4 alkyl or C1-4alkyl substituted by 1 of hydroxy or --CH₂ OH, ##STR4## in which A^(A)is single bond or C1-4 alkylene or ##STR5## in which A^(A) is ##STR6##in which mA is 0, 1, 2, 3, 4, nA is 0, 1, 2, 3, 4, and mA+nA is 2, 3, 4,B^(A) is --NR^(3A) SO₂ -- or --SO₂ NR^(3A) --in which R^(3A) ishydrogen, C1-4 alkyl or --CH₂ COOR^(7A) in which R^(7A) is hydrogen orR^(4aA), in which R^(4aA) is C1-4 alkyl,

R^(2A) is (i) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl,

(ii) C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl substituted by 1, 2 or 3of phenyl, C4-7 cycloalkyl or phenyl substituted by 1, 2 or 3substituents selected from C1-4 alkyl, C1-4 alkoxy or halogen or

(iii) naphthyl,

in the formula ##STR7## or non-toxic salts thereof, are useful as PGE₂antagonist or agonist.

As for different activity case, in the specification of EP-0578847(corresponding to JP Patent Application Kokai Hei 6-25074), it isdisclosed that the compounds of the formula (B) ##STR8## R^(1B) ishydrogen or C1-4 alkyl, R^(2B) is hydrogen, C1-6 alkyl or phenyl,

R^(3B) is

(i) C1-15 alkyl,

(ii) C1-8 alkyl substituted by 1 or 2 of benzene ring, C4-7 cycloalkylor 4-7 membered monocyclic ring containing one nitrogen,

(iii) C10-15 fused tricyclic ring,

e^(B) is an integer of 3-5,

f^(B) is an integer of 1-3,

p^(B) is 0 or an integer of 1-4,

q^(B) is 0, 1 or2,

s^(B) is 0 or an integer of 1-3;

with the proviso that, when ##STR9## is (iii) or (iv), --(CH₂)p^(B) -and =CH--(CH₂)s^(B) -- is bonded at the position a or b on the ring, andthe ring in R^(3B) may be substituted by one to three of C1-4 alkyl,C1-4 alkoxy, halogen, nitro or trihalomethyl, are useful as PGI₂agonist.

In the specification of JP Patent Application Kokai Sho61-267532(corresponding to EP-181568), it is disclosed that thecompounds of the formula (D)

    Ar.sup.1D -X.sup.D -Ar.sup.D -Z.sup.D -(R.sup.D)n.sup.D'   (D)

wherein Ar^(1D) is a nitrogen, sulfur or oxygen containing heterocyclicring or an aromatic ring,

Ar^(D) is a phenyl or nitrogen, oxygen or sulfur containing heterocyclicring,

Ar^(1D) and Ar may be fully substituted or less than fully substitutedby H, CH₃, lower alkyl, aryl, aralkyl, halogen, hydroxy, lower alkoxy,CF₃, COOH, alkylcarboxy, arylcarboxy, alkylcarbalkoxy, alkanoyl, formyl,oxo, nitrdlo, amino, aminoalkyl, alkylamine, carboxyamide, aryloxy,nitro, sulfonyl, sulfonamide, thio, alkylthio, hydroxyalkyl oroxyalkylcarboxy,

X^(D) is --O(CHR^(1D))n^(D) --, --S(O)n^(D") -(CHR^(1D))n^(D) --,--NR^(1D) (CHR^(1D))n^(D) -alkylene of up to 2 carbon atoms in theprincipal chain and up to a total 4 carbon atoms,--C(R^(1D))=(CR^(1D))--, --C.tbd.C--, --CO(CHR^(1D))n^(D') --,--CH(OH)--(CHR^(1D))n^(D) --, --CH=N--, --CO--O--, --CO--S--, or--CO--N(R^(1D))--,

Z^(D) is an alkylene containing up to 10 carbon atoms in principal chainand a total of up to 12 carbon atoms and from 0 to 2 double bonds andthe said alkylene chain may be attached to Ar^(D) through an oxygen,sulfur or amino nitrogen atom,

and when n^(D') is 2 or more, one of the R^(D) substituents may behalogen on an omega carbon of the alkylene chain Z^(D),

when n D' is 1, RD is a substituent attached to one of the carbon atomsof Z^(D) selected from the group consisting of oxo, OR^(3D), SR^(3D),N(R^(2D))₂, R^(1D) and --CO R^(4D),

when n D' is 2 or more, one R^(D) is as previously defined, and theother R^(D) is a substituent attached to one of the carbon atoms ofZ^(D) selected from the group consisting of oxo, OR^(3D), SR^(3D),N(R^(2D))₂, --COR^(4D), lactone and halogen,

R^(1D) is H or CH₃,

R^(2D) is H, lower alkyl, aryl or aralkyl,

R^(3D) is H, lower alkyl, lower alkanoyl, aryl, aralkyl or substitutedaryl in which the substituent is halogen, lower alkyl or lower alkoxy,

R^(4D) is O R^(2D) or N(R^(2D))₂,

n^(D) is 0 or 1,

n^(D') is an integer of 1-7,

n D" is 0, 1 or 2,

possess the anti-inflammatory and anti-allergic activity due tolipoxygenase inhibition.

In addition, in the specification of (E) U.S. Pat. No. 4,327,022, (F) JPPatent Application Kokai Sho 50-89352 and (G) U.S. Pat. No. 3,930,672,it is disclosed that the naphthol derivatives are useful as (1)cardiotonic or anti-bacterial agents, (2) analgesic, anti-inflammatoryand antipyretic agent and (3) starting material of the compound relatedto copy paper, respectively.

DISCLOSURE OF THE INVENTION

Purpose of the Invention

The present inventors have been studying in order to find out PGE₂antagonist or agonist which have new skeleton in structure, and thenhave found out that the naphthyloxy acetic acid derivatives (compoundsof the formula (I) as mentioned hereinafter) in which thioether,sulfinyl, sulfonyl, ether or amine are introduced into the side chainare useful as PGE₂ antagonist or agonist, particularly, the mentionedcompounds can bind the EP₃ receptor strongly. And then, the presentinvention has been completed.

Comparison with Related Art

The compounds of the formula (A) as mentioned in Related Art possess--NR^(3A) SO₂ -- or --SO₂ NR^(3A) wherein all symbols are the samemeaning as defined hereinbefore, in the side chain as basic structure.On the other hand, corresponding part in the present invention compoundsis thioether, sulfinyl, sulfonyl, ether or amine.

The compounds of the formula (B), (D) and the compounds described in(E), (F) and (G) as mentioned in Related Art possess (1) PGI₂ agnosticactivity, (2) anti-inflammatory and anti-allergic activity due tolipoxygenase inhibition (3) cardiotonic or anti-bacterial agents, (4)analgesic, anti-inflammatory and antipyretic agent and (5) startingmaterial of the compound related to copy paper, respectively. On theother hand, the present invention compounds possess the PGE₂antagonistic or agonistic activity.

That is to say, the present invention provides:

1) a naphthyloxyacetic acid derivative of the formula (I) ##STR10##wherein A is (i) hydrogen,

(ii) --(C1-4 alkylene)--COOR¹ in which R¹ is hydrogen or C1-4 alkyl,

(iii) --(C1-4 alkylene)--CONR² R³ in which R² and R³ each,independently, is hydrogen or C1-4 alkyl,

(iv) --(C1-4 alkylene)--OH,

(v) --(C1-4 alkylene)-tetrazolyl or

(vi) --(C1-4 alkylene)--CN;

E is

(i) single bond or

(ii) C1-6 alkylene;

G is --S--, --SO--, --SO₂ --, --O-- or --NR⁴ -- in which, R⁴ is hydrogenor C1-4 alkyl;

L is

(i) C1-6 alkylene,

(ii) --(CH₂)_(m) --CH=CH--(CH₂)_(n) -- in which m is 0 or an integer of1-3, n is 0 or an integer of 1-3 or

(iii) --(CH₂)_(m) --CH(OH)--(CH₂)_(y) -- in which x is an integer of1-3, y is 0 or an integer of 1-3; ##STR11## in which each phenyl groupmay be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro ortrifluoromethyl;

in the formula ##STR12## with the proviso that, (1) when G is --SO--or--SO₂ --, M is neither ##STR13## in which each phenyl group may besubstituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro ortrifluoromethyl,

(2) when m in L is 0, G is --SO-- or --SO₂ --,

(3) when n in L is 0, M is ##STR14## in which each phenyl group may besubstituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro ortrifluoromethyl,

(4) when y in L is 0, M is ##STR15## in which each phenyl group may besubstituted by 1-3 of C1-4 alkyl, C1-4 alkoxy, halogen, nitro ortrifluoromethyl,

(5) when A is hydrogen, L is --(CH₂)_(m) --CH=CH--(CH₂)_(n) -- in whichm and n are the same meaning as hereinbefore defined, or --(CH₂)_(x)--CH(OH)--(CH₂)_(y) in which x and y are the same meaning ashereinbefore defined, and

(6) tetrazolyl in A is ##STR16## or non-toxic salt thereof, non-toxicacid addition salt thereof or their hydrate,

2) a compound described in 1), wherein A is --(C1-4 alkylene)--COOR¹,

3) a compound described in 1), wherein A is --(C1-4 alkylene)--CONR² R³,--C1-4 alkylene)--OH, --(C1-4 alkylene)-tetrazolyl or --(C1-4alkylene)--CN,

4) a compound described in 1), wherein A is hydrogen,

5) a compound described in 1)-5), wherein L is --(CH₂)_(m)--CH=CH--(CH₂)_(n) or --(CH₂)_(x) --CH(OH)--(CH₂)_(y) --,

6) a compound described in 5), wherein G is --S--, --SO-- or --SO₂ --,

7) a compound described in 5), wherein G is --O--,

8) a compound described in 5), wherein G is --NR⁴ --,

9) a compound described in 6), which is

(1) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2RS-propanol,

(2) 1-[2-(5-hydroxy-1-naphthyl)ethylsulfinyl]-3-phenoxy-2RS-propanol,

(3) 1-[2-(5-hydroxy-1-naphthyl)ethylsulfonyl]-3-phenoxy-2RS-propanol,

(4) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2R-propanol,

(5) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2S-propanol,

(6) 1-(5-hydroxy-1-naphthyl)methylthio-3-phenoxy-2RS-propanol,

(7) 1-(5-hydroxy-1-naphthyl)methylsulfinyl-3-phenoxy-2RS-propanol,

(8) 1-(5-hydroxy-1-naphthyl) methylsulfonyl-3-phenoxy-2RS-propanol,

(9) 2-[3-(5-hydroxy-1-naphthyl)propylthio]-1-phenyl-1RS-ethanol,

(10) 2-[3-(5-hydroxy-1-naphthyl)propylsulfinyl]-1-phenyl-1RS-ethanol,

(11) 2-[3-(5-hydroxy-1-naphthyl)propylsulfonyl]-1-phenyl-1RS-ethanol,

(12) 1-(5-hydroxy-1-naphthyl)thio-3-phenoxy-2RS-propanol,

(13) 1-(5-hydroxy-1-naphthyl)sulfinyl-3-phenoxy-2RS-propanol,

(14) 1-(5-hydroxy-1-naphthyl)sulfonyl-3-phenoxy-2RS-propanol,

(15)1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-chlorophenoxy)-2RS-propanol,

(16)1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methylphenoxy)-2RS-propanol,

(17)1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methoxyphenoxy)-2RS-propanol,

(18)1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-diphenylmethoxy-2RS-propanol,

(19)1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-[1-phenyl-1-(4-chlorophenyl]-methoxyl-2RS-propanol,

(20) 1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenylthio-2RS-propanol,

(21) 1-(5-hydroxy-1naphthyl)methylthio-3-diphenylmethoxy-2RS-propanol,

(22)1-(5-hydroxy-1-naphthyl)methylthio-3-[1-phenyl-1-(4-chlorophenyl)-methoxy]-2RS-propanol,

(23)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid methyl ester,

(24) 2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic acid methylester,

(25)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}-aceticacid methyl ester,

(26) 2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester,

(27) 2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester,

(28) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]aceticacid methyl ester,

(29)2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]aceticacid methyl ester,

(30)2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]aceticacid methyl ester,

(31) 2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}aceticacid methyl ester,

(32)2-{5-[3-(2RS-hydroxy-2-phenylethylsulfinyl)propyl]-1-naphthyloxy}aceticacid methyl ester,

(33)2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1naphthyloxy}aceticacid methyl ester,

(34) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acidmethyl ester,

(35) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]aceticacid methyl ester,

(36) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]aceticacid methyl ester,

(37) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid methylester,

(38) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid methylester,

(39)2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester,

(40)2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester,

(41)2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester,

(42)2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester,

(43)2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-ethyl]-1-naphthyloxy}aceticacid methyl ester,

(44)2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester,

(45)2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-naphthyloxy]aceticacid methyl ester,

(46)2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]-methyl-1-naphthyloxy}aceticacid methyl ester,

(47)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}aceticacid,

(48)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}aceticacid,

(49)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}-aceticacid,

(50) 2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}aceticacid,

(51) 2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}aceticacid,

(52) 2-[5-(2RS-hydroxy-3-phenoxypropylthio) methyl-1-naphthyloxy]aceticacid,

(53)2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]aceticacid,

(54)2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]aceticacid,

(55) 2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}aceticacid,

(56) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid,

(57) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]aceticacid,

(58) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]aceticacid,

(59) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid,

(60) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid,

(61)2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid,

(62)2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid,

(63)2-{5-[2-(2RS-hydroxy-3-(4-methyoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid,

(64)2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}aceticacid,

(65)2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}aceticacid,

(66)2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]aceticacid,

(67)1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)-ethyl]naphthalene,

(68) 1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-chlorophenoxy)propylthio]ethyl}naphthalene,

(69)1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methylphenoxy)propylthio]ethyl}naphthalene,

(70)1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methoxyphenoxy)propylthio]ethyl}naphthalene,

(71)1-cyanomethoxy-5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)-ethyl]naphthalene,

(72)1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]naphthalene,

(73)1-cyanomethoxy-5-(2RS-hydroxy-3-diphenylmethoxypropylthiomethyl)naphthalene,

(74)2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)ethyl]-1-naphthyloxy}ethanol,

(75)2-{5-[2-(2RS-hydroxy-3-phenylaminopropylthio)ethyl]-1-naphthyloxy}ethanol,

(76)1-(tetrazol-5-ylmethoxy)-5-{2-[2RS-hydroxy-3-(4-methyoxyphenoxy)-propylthio]ethyl}naphthalene,

(77)N-methyl-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)-propylthio]methyl-1-naphthyloxy}aceticacid amide,

(78)1-{2-[5-hydroxy-1-(1,2,3,4-tetrahydronaphthyl)]ethylthio}-3-phenoxy-2RS-propanol,

(79)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydronaphthyloxy)}aceticacid methyl ester,

(80)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydronaphthyloxy)}aceticacid or

(81)1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-5,6,7,8-tetrahydronaphthalene,

10) a compound described in 7), which is

(1) 1-[2-(5-hydroxy-1-naphthyl)ethoxy]-3-phenoxy-2RS-propanol,

(2) 2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}aceticacid methyl ester or

(3) 2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}aceticacid,

11) a compound described in 8), which is

(1) 1-[2-(5-hydroxy-1-naphthyl)ethylamino]-3-phenoxy-2RS-propanol or

(2)2-{5-[2-(2RS-hydroxy-3-phenoxypropylamino)ethyl]-1-naphthyloxy}aceticacid,

12) a pharmaceutical composition which comprises a naphthyloxyaceticacid derivative of the formula (I) depicted in 1), non-toxic saltthereof, non-toxic acid addition salt thereof or their hydrate as anactive ingredient, and

13) a pharmaceutical composition (PGE₂ antagonist or agonist) whichcomprises a naphthyloxyacetic acid derivative of the formula (I)depicted in 1), non-toxic salt thereof, non-toxic acid addition saltthereof or their hydrate as an active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

In the formula (I), C1-4 alkyl represented by R¹, R², R³ and R⁴, or C1-4alkyl represented as substituent of phenyl in M means methyl, ethyl,propyl, butyl and isomeric groups thereof.

In the formula (I), C1-4 alkylene in A means methylene, ethylene,trimethylene, tetramethylene and isomeric groups thereof.

In the formula (I), C1-6 alkylene represented by E and L meansmethylene, ethylene, trimethylene, tetramethylene, pentamethylene,hexamethylene and isomeric groups thereof.

In the formula (1), C1-4 alkoxy in M means methoxy, ethoxy, propoxy,butoxy and isomeric groups thereof.

In the formula (I), halogen in M means chlorine, bromine, fluorine andiodine.

In the formula (I), the side chain represented by --O--A may beconnected with any carbon atom at 1st to 4th position, preferably, at1st position.

In the formula (I), the side chain represented by -E-G-L-M may beconnected with any carbon atom at 5th to 8th position, preferably, at5th or 6th position.

Unless otherwise, specified all isomers are included in the invention.For example, alkyl, alkylene and alkenylene includes straight-chain orbranched-chain ones. Double bond in alkenylene include structure ofconfigurations E, Z and EZ mixtures. Isomers generated by asymmetriccarbon(s) e.g. branched alkyl are also included in the presentinvention. In addition, isomers generated by sulfinyl are also includedin the present invention.

Salts

The compounds of the present invention of the formula (I) may beconverted into the corresponding salts by known methods per se.Non-toxic and water-soluble salts are preferable. Suitable salts, forexample, are as follows. salts of alkaline metals (potassium, sodiumetc.), salts of alkaline earth metals (calcium, magnesium etc.),ammonium salts, salts of pharmaceutically acceptable organic amines(tetramethylammonium, triethylamine, methylamine, dimethylamine,cyclopentylamine, benzylamine, phenethylamine, piperidine,monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane,lysine, arginine, N-methyl-D-glucamine etc.).

Acid addition salts

The compounds of the formula (I) may be converted into the correspondingacid addition salts by methods known per se. Non-toxic and water-solubleacid addition salts are preferable. Suitable acid addition salts, forexample, are salts of inorganic acids, e.g., hydrochloride,hydrobromide, hydroiodide, sulphate, phosphate, nitrate etc., or saltsof organic acids, e.g., acetate, trifluoroacetate, lactate, tartarate,oxalate, fumarate, maleate, citrate, benzoate, methanesulphonate,ethanesulphonate, benzenesulphonate, toluenesulphonate, isethioate,glucuronate, gluconate etc.

Preferable compound

In the compounds of the formula (I) of the present invention, thecompounds wherein L is --(CH₂)_(m) --CH=CH--(CH₂)_(n) -- in which m andn are the same meaning as hereinbefore defined, or --(CH₂)_(x)--CH(OH)--(CH₂)_(y) -- in which x and y are the same meaning ashereinbefore defined, are preferable. The compounds wherein L is--CH=CH-- or --CH₂ --CH(OH)--CH₂ --, are more preferable.

Concretely, the following compounds are preferable.

The compounds of the formula (IA) ##STR17## The compounds of the formula(IB) ##STR18## The compounds of the formula (IC) ##STR19## The compoundsof the formula (ID) ##STR20## The compounds of the formula (IE)##STR21## The compounds of the formula (IF) ##STR22## The compounds ofthe formula (IG) ##STR23## The compounds of the formula (IH) ##STR24##The compounds of the formula (IJ) ##STR25## The compounds of the formula(IK) ##STR26## The compounds of the formula (IL) ##STR27## The compoundsof the formula (IM) ##STR28## The compounds of the formula (IN)##STR29## The compounds of the formula (IO) ##STR30##

In the formula (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ),(IK), (IL), (IM), (IN) and (IO), all symbols are the same meaning ashereinbefore defined.

The compounds described in Example and the following compounds arepreferable particularly.

    ______________________________________                                                                      (IA)                                                                            #STR31##                                      No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR32##                                                     - 2 --S--                                                                                      #STR33##                                                     - 3 --S--                                                                                      #STR34##                                                     - 4 --SO--                                                                                     #STR35##                                                     - 5 --SO--                                                                                     #STR36##                                                     - 6 --SO--                                                                                     #STR37##                                                     - 7 --SO.sub.2 --                                                                              #STR38##                                                     - 8 --SO.sub.2 --                                                                              #STR39##                                                     - 9 --SO.sub.2 --                                                                              #STR40##                                                     - 10  --NH--                                                                                  ##STR41##                                                  ______________________________________                                    

    ______________________________________                                                                      (IB)                                                                            #STR42##                                      No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR43##                                                     - 2 --S--                                                                                      #STR44##                                                     - 3 --S--                                                                                      #STR45##                                                     - 4 --SO--                                                                                     #STR46##                                                     - 5 --SO--                                                                                     #STR47##                                                     - 6 --SO--                                                                                     #STR48##                                                     - 7 --SO.sub.2 --                                                                              #STR49##                                                     - 8 --SO.sub.2 --                                                                              #STR50##                                                     - 9 --SO.sub.2 --                                                                              #STR51##                                                     - 10  --NH--                                                                                  ##STR52##                                                  ______________________________________                                    

    ______________________________________                                                                      (IC)                                                                            #STR53##                                      No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR54##                                                     - 2 --S--                                                                                      #STR55##                                                     - 3 --S--                                                                                      #STR56##                                                     - 4 --SO--                                                                                     #STR57##                                                     - 5 --SO--                                                                                     #STR58##                                                     - 6 --SO--                                                                                     #STR59##                                                     - 7 --SO.sub.2 --                                                                              #STR60##                                                     - 8 --SO.sub.2 --                                                                              #STR61##                                                     - 9 --SO.sub.2 --                                                                              #STR62##                                                     - 10  --NH--                                                                                  ##STR63##                                                  ______________________________________                                    

    ______________________________________                                                                      (ID)                                                                            #STR64##                                      No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR65##                                                     - 2 --S--                                                                                      #STR66##                                                     - 3 --S--                                                                                      #STR67##                                                     - 4 --SO--                                                                                     #STR68##                                                     - 5 --SO--                                                                                     #STR69##                                                     - 6 --SO--                                                                                     #STR70##                                                     - 7 --SO.sub.2 --                                                                              #STR71##                                                     - 8 --SO.sub.2 --                                                                              #STR72##                                                     - 9 --SO.sub.2 --                                                                              #STR73##                                                     - 10  --NH--                                                                                  ##STR74##                                                  ______________________________________                                    

    ______________________________________                                                                      (IE)                                                                            #STR75##                                      No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR76##                                                     - 2 --S--                                                                                      #STR77##                                                     - 3 --S--                                                                                      #STR78##                                                     - 4 --SO--                                                                                     #STR79##                                                     - 5 --SO--                                                                                     #STR80##                                                     - 6 --SO--                                                                                     #STR81##                                                     - 7 --SO.sub.2 --                                                                              #STR82##                                                     - 8 --SO.sub.2 --                                                                              #STR83##                                                     - 9 --SO.sub.2 --                                                                              #STR84##                                                     - 10  --NH--                                                                                  ##STR85##                                                  ______________________________________                                    

    ______________________________________                                                                      (IF)                                                                            #STR86##                                      No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR87##                                                     - 2 --S--                                                                                      #STR88##                                                     - 3 --S--                                                                                      #STR89##                                                     - 4 --SO--                                                                                     #STR90##                                                     - 5 --SO--                                                                                     #STR91##                                                     - 6 --SO--                                                                                     #STR92##                                                     - 7 --SO.sub.2 --                                                                              #STR93##                                                     - 8 --SO.sub.2 --                                                                              #STR94##                                                     - 9 --SO.sub.2 --                                                                              #STR95##                                                     - 10  --NH--                                                                                  ##STR96##                                                  ______________________________________                                    

    ______________________________________                                                                      (IG)                                                                            #STR97##                                      No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR98##                                                     - 2 --S--                                                                                      #STR99##                                                     - 3 --S--                                                                                      #STR100##                                                    - 4 --SO--                                                                                     #STR101##                                                    - 5 --SO--                                                                                     #STR102##                                                    - 6 --SO--                                                                                     #STR103##                                                    - 7 --SO.sub.2 --                                                                              #STR104##                                                    - 8 --SO.sub.2 --                                                                              #STR105##                                                    - 9 --SO.sub.2 --                                                                              #STR106##                                                    - 10  --NH--                                                                                  ##STR107##                                                 ______________________________________                                    

    ______________________________________                                                                      (IH)                                                                            #STR108##                                     No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR109##                                                    - 2 --S--                                                                                      #STR110##                                                    - 3 --S--                                                                                      #STR111##                                                    - 4 --SO--                                                                                     #STR112##                                                    - 5 --SO--                                                                                     #STR113##                                                    - 6 --SO--                                                                                     #STR114##                                                    - 7 --SO.sub.2 --                                                                              #STR115##                                                    - 8 --SO.sub.2 --                                                                              #STR116##                                                    - 9 --SO.sub.2 --                                                                              #STR117##                                                    - 10  --NH--                                                                                  ##STR118##                                                 ______________________________________                                    

    ______________________________________                                                                      (IJ)                                                                            #STR119##                                     No.       G        M                                                          ______________________________________                                          1 --SO--                                                                                         #STR120##                                                   - 2 --SO--                                                                                      #STR121##                                                   - 3 --SO.sub.2 --                                                                               #STR122##                                                   - 4 --SO--                                                                                      #STR123##                                                   - 5 --SO--                                                                                      #STR124##                                                   - 6 --SO--                                                                                      #STR125##                                                   - 7 --SO.sub.2 --                                                                               #STR126##                                                   - 8 --SO.sub.2 --                                                                               #STR127##                                                   - 9 --SO.sub.2 --                                                                               #STR128##                                                   - 10  --SO--                                                                                   ##STR129##                                                ______________________________________                                    

    ______________________________________                                                                      (IK)                                                                            #STR130##                                     No.       G        M                                                          ______________________________________                                          1 --SO--                                                                                         #STR131##                                                   - 2 --SO--                                                                                      #STR132##                                                   - 3 --SO.sub.2 --                                                                               #STR133##                                                   - 4 --SO--                                                                                      #STR134##                                                   - 5 --SO--                                                                                      #STR135##                                                   - 6 --SO--                                                                                      #STR136##                                                   - 7 --SO.sub.2 --                                                                               #STR137##                                                   - 8 --SO.sub.2 --                                                                               #STR138##                                                   - 9 --SO.sub.2 --                                                                               #STR139##                                                   - 10  --SO--                                                                                   ##STR140##                                                ______________________________________                                    

    ______________________________________                                                                      (IL)                                                                            #STR141##                                     No.       G        M                                                          ______________________________________                                          1 --SO--                                                                                         #STR142##                                                   - 2 --SO--                                                                                      #STR143##                                                   - 3 --SO.sub.2 --                                                                               #STR144##                                                   - 4 --SO--                                                                                      #STR145##                                                   - 5 --SO--                                                                                      #STR146##                                                   - 6 --SO--                                                                                      #STR147##                                                   - 7 --SO.sub.2 --                                                                               #STR148##                                                   - 8 --SO.sub.2 --                                                                               #STR149##                                                   - 9 --SO.sub.2 --                                                                               #STR150##                                                   - 10  --SO--                                                                                   ##STR151##                                                ______________________________________                                    

    ______________________________________                                                                      (IM)                                                                            #STR152##                                     No.       G        M                                                          ______________________________________                                          1 --SO--                                                                                         #STR153##                                                   - 2 --SO--                                                                                      #STR154##                                                   - 3 --SO.sub.2 --                                                                               #STR155##                                                   - 4 --SO--                                                                                      #STR156##                                                   - 5 --SO--                                                                                      #STR157##                                                   - 6 --SO--                                                                                      #STR158##                                                   - 7 --SO.sub.2 --                                                                               #STR159##                                                   - 8 --SO.sub.2 --                                                                               #STR160##                                                   - 9 --SO.sub.2 --                                                                               #STR161##                                                   - 10  --SO--                                                                                   ##STR162##                                                ______________________________________                                    

    ______________________________________                                                                      (IN)                                                                            #STR163##                                     No.      G        M                                                           ______________________________________                                          1 --S--                                                                                         #STR164##                                                    - 2 --S--                                                                                      #STR165##                                                    - 3 --S--                                                                                      #STR166##                                                    - 4 --SO--                                                                                     #STR167##                                                    - 5 --SO--                                                                                     #STR168##                                                    - 6 --SO--                                                                                     #STR169##                                                    - 7 --SO.sub.2 --                                                                              #STR170##                                                    - 8 --SO.sub.2 --                                                                              #STR171##                                                    - 9 --SO.sub.2 --                                                                              #STR172##                                                    - 10  --NH--                                                                                  ##STR173##                                                 ______________________________________                                    

    ______________________________________                                                                      (IO)                                                                            #STR174##                                     No.         G        A                                                        ______________________________________                                          1 --S--                                                                                            #STR175##                                                 - 2 --S--                                                                                         #STR176##                                                 - 3 --S--                                                                                         #STR177##                                                 - 4 --SO--                                                                                        #STR178##                                                 - 5 --SO--                                                                                        #STR179##                                                 - 6 --SO--                                                                                        #STR180##                                                 - 7 --SO.sub.2 --                                                                                 #STR181##                                                 - 8 --SO.sub.2 --                                                                                 #STR182##                                                 - 9 --SO.sub.2 --                                                                                 #STR183##                                                 - 10  --NH--                                                                                      #STR184##                                                 - 11  --S--                                                                                      ##STR185##                                              ______________________________________                                    

Method of preparation for the compounds of the present invention

In the compounds of the formula (I) of the present invention, thecompounds of the formula (I-1) ##STR186## wherein all symbols are thesame meaning as hereinbefore defined may be prepared by the followingmethods (a)-(b).

(a) In the compounds of the formula (I-1) of the present invention, thecompounds wherein L is --(CH₂)_(x) --CH(OH)--(CH₂)_(y) -- or C1-6alkylene, i.e., the compounds of the formula (I-1a) ##STR187## whereinL^(a) is --(CH₂)_(x) --CH(OH)--(CH₂)_(y) -- or C1-6 alkylene, and theother symbols are the same meaning as hereinbefore defined may beprepared from the compounds of the formula (II-a) ##STR188## whereinL^(aa) is --(CH₂)_(x) --CH(OR^(aa))--(CH₂)_(y) -- in which, R^(aa) isthe protecting group which may be removed in an acidic condition, forexample, tetrahydropyranyl etc., or C1-6 alkylene, R^(a) is theprotecting group which may be removed in an acidic condition or analkaline condition, for example, methoxymethyl or ethylcarbonate etc.,and the other symbols are the same meaning as hereinbefore defined, withthe proviso that when nitrogen atom in G or M in the formula (I-1a) isfree --NH group, NH group in the formula (II-a) is protected by thewell-known protecting group (for example, benzyloxycarbonyl (cbz),t-butoxycarbonyl (boc) or trifluoroacetyl (COCF₃) etc.) by removal ofhydroxy-protecting group in an acidic condition, or removal ofhydroxy-protecting group in an acidic condition and an alkalinecondition two times, succeedingly, (Which reaction may be startedfirst.), if necessary, followed by removal of NH-protecting group.

This reaction may be carried out by known methods. For example, theremoval of hydroxy-protecting group in an acidic condition may becarried out in a water-miscible organic solvent (methanol, ethanol,tetrahydrofuran (THF) etc.), by using organic acid (acetic acid,p-toluene sulfonic acid, trifluoro acetic acid or trichloro acetic acidetc.) or inorganic acid (hydrochloric acid or hydrobromic acid etc.), at0-90° C. The removal of hydroxy-protecting group in an alkalinecondition may be carried out in an organic solvent (methanol, ethanol,dimethoxyethane or mixture thereof etc.), using an aqueous solution ofhydroxide of alkali (sodium hydroxide, potassium hydroxide etc.),hydroxide of alkaline-earth metals (calcium dihydroxide etc.) orcarbonate (potassium carbonate etc.) at 0-50° C.

As for removal of NH-protecting group, for example, the removal of cbzgroup may be carried out under an atmosphere of hydrogen gas, in anorganic solvent (methanol, ethanol or THF etc.), by using catalyst(Pd-C, Pd or Ni etc.), at 0-50° C. The removal of boc may be carried outin a water-miscible organic solvent (methanol, ethanol or THF etc.), byusing organic acid (acetic acid, p-toluene sulfonic acid, trifluoroacetic acid or trichloro acetic acid etc.) or inorganic acid(hydrochloric acid or hydrobromic acid etc.), at 0-90° C. The removal ofCOCF₃ may be carried out, for example, in a water-miscible organicsolvent (methanol, ethanol, THF, dimethoxyethane or mixture thereofetc.), using an aqueous solution of hydroxide of alkali (sodiumhydroxide, potassium hydroxide etc.), hydroxide of alkaline-earth metals(calcium dihydroxide etc.) or carbonate (potassium carbonate etc.) at0-50° C.

(b) In the present invention compounds of the formula (I-1), thecompounds wherein L is --(CH₂)_(m) --CH=CH--(CH₂)_(n) --, i.e., thecompounds of the formula (I-1b) ##STR189## wherein L^(b) is --(CH₂)_(m)--CH=CH--(CH₂)_(n) --, and the other symbols are the same meaning ashereinbefore defined may be prepared from the compounds of the formula(II-b) ##STR190## wherein L^(bb) is --(CH₂)_(m) --CH₂CH(OR^(b))--(CH₂)_(n) -- in which, R^(b) is the well-known eliminationgroup (for example, mesyl or tosyl group etc.), and the other symbolsare the same meaning as hereinbefore defined, with the proviso that whennitrogen atom in G or M in the formula (I-1b) is free --NH group, NHgroup in the formula (II-b) is protected by the well-known protectinggroup (for example, cbz, boc or COCF₃ etc.) by removal of eliminationgroup, if necessary, followed by removal of NH-protecting group.

This reaction may be carried out in an organic solvent (methanol orethanol etc.) by adding base (potassium hydroxide, sodium hydroxide ortriethylamine etc.) at 0-100° C. The removal of NH-protecting group maybe carried out by the method described hereinbefore.

In the compound of the formula (I) of the present invention, thecompounds of the formula (I-2) of the present invention ##STR191##wherein A² is the same meaning as A other than hydrogen may be preparedby reacting the compounds, in which nitrogen atom in G or M in theformula (I-1) is free --NH group, NH group is protected by thewell-known protecting group (for example, cbz, boc or COCF₃ etc.), i.e.the compounds of the formula (II-c) ##STR192## wherein G^(a) and M^(a)are the same meaning as G and M, respectively, with the proviso thatwhen nitrogen atom in G or M in the formula (I-2) is free --NH group, NHgroup is protected by the well-known protecting group (for example, cbz,boc or COCF₃ etc.) and the other symbols are the same meaning ashereinbefore defined with the compounds of the formula (III)

    X.sup.2 --A.sup.2a                                         (III)

wherein X² is halogen and A^(2a) is

(i) --(C1-4 alkylene)-COOR^(1a) in which R^(1a) is C1-4 alkyl,

(ii) --(C1-4 alkylene) --OR⁵, in which R⁵ is tetrahydropyranyl,

(iii) --(C1-4 alkylene) --CONR² R³,

(iv) --(C1-4 alkylene)-tetrazolyl or

(v) --(C1-4 alkylene)--CN,

and the other symbols are the same meaning as hereinbefore defined, withthe proviso that when nitrogen atom in A^(2a) is free --NH group, NHgroup is protected by the well-known protecting group (for example, cbz,boc or COCF₃ etc.),

if necessary, followed by hydrolysis in an alkaline condition or byremoval of protecting group.

The above mentioned O-alkylation is known, and for example, thisreaction may be carried out in a water-miscible organic solvent(acetone, THF or methylene chloride etc.) in the presence of a base(potassium carbonate etc.), at 0-50° C.

The hydrolysis in an alkaline condition is well known. For example, thisreaction may be carried out in a water-miscible organic solvent(methanol, ethanol, dimethoxyethane or mixture thereof etc.), using anaqueous solution of hydroxide of alkali (sodium hydroxide, potassiumhydroxide etc.), hydroxide of alkaline-earth metals (calcium dihydroxideetc.) or carbonate (potassium carbonate etc.) at 0-50° C. The removal ofprotecting group may be carried out by the method describedhereinbefore.

In the compounds of the formula (I) of the present invention, thecompounds wherein A is --(C1-4 alkylene)-tetrazol-5-yl, i.e. thecompounds of the formula (I-3) ##STR193## in which, A³ is --(C1-4alkylene)-tetrazol-5-yl and the other symbols are the same meaning ashereinbefore defined may be also prepared by reacting the compounds ofthe formula (1-4) ##STR194## in which A⁴ is --(C1-4 alkylene)--CN andthe other symbols are the same meaning as hereinbefore defined with theazide.

The reaction to introduce a tetrazol-5-yl group from cyano group with anazide are known, it may be carried out, for example, on anhydrouscondition, using with azide (sodium azide, lithium azide, potassiumazide etc.) in the presence of weak acid (pyridium chloride, ammoniumchloride, dimethylaniline hydrochloride etc.) in an inert organicsolvent (DMF, N-methylpyrrolidone etc.) with heating.

In the compounds of the formula (I) of the present invention, thecompounds wherein A is --(C1-4 alkylene)--CONR² R³, i.e. the compoundsof the formula (I-5) ##STR195## in which, A⁵ is --(C1-4 alkylene)--CONR²R³ in which R² and R³ are the same meaning as hereinbefore defined andthe other symbols are the same meaning as hereinbefore defined may bealso prepared by reacting the compounds of the formula (I-6) ##STR196##in which A⁶ is --(C1-4 alkylene)--COOR^(1a) in which R^(1a) is the samemeaning as hereinbefore defined and the other symbols are the samemeaning as hereinbefore defined with the compounds of the formul

    HNR.sup.2 R.sup.3                                          (IX)

in which all symbols are the same meaning as hereinbefore defined.

The above reaction to form an amide bond is well known. For example,this reaction may be carried out in inert organic solvent (benzene,toluene or methylene chloride etc.), or in the absence of solvent, usingtertiary amine (pyridine or triethylamine etc.) at 0-50° C., or it maybe carried out in an organic solvent (methylene chloride or THF etc.),using a corresponding base, in the presence or absence of correspondingcondensing agents (2-chloro-N-methylpyridinium iodide etc.) at 0-40° C.

The compounds of the formula (II-a) and (II-b) may be prepared by theknown reaction. For example, these compounds may be prepared accordingto the method shown in the reaction scheme (1), (2), (3) or (4) ormethod described in Example.

In the compounds of the formula (I-1) of the present invention, thecompounds wherein G is --NH-- and L is --CH₂ --CH(OH)--(CH₂)_(y) --,i.e. the compounds of the formula ##STR197## in which L^(d) is --CH₂--CH(OH)--(CH₂)_(y) -- in which y is the same meaning as hereinbeforedefined and the other symbols are the same meaning as hereinbeforedefined may be also prepared according to the method shown in thereaction scheme (5) or method described in Example.

In the compounds of the formula (I) of the present invention, thecompounds wherein M is ##STR198## in which each phenyl may besubstituted by the substituent described hereinbefore and L is--(CH₂)_(x) --CH(OH)--(CH₂)_(y) --, i.e. the compounds of the formula##STR199## in which M^(b) is ##STR200## in which each phenyl may besubstituted by the substituent described hereinbefore, L^(e) is--(CH₂)_(x) --CH(OH)--(CH₂)_(y) -- in which x and y are the same meaningas hereinbefore defined, G³ is --S--, --O-- or --NR⁴ -- and the othersymbols are the same meaning as hereinbefore defined may be alsoprepared according to the method shown in the reaction scheme (6) ormethod described in Example.

In reaction scheme (1), (2), (3), (4), (5) and (6) each symbol means thefollowing definition or is the same meaning as defined hereinbefore.

Et is ethyl,

Ac is acetyl,

iPr is isopropyl.

Ph is phenyl,

MOM is methoxymethyl,

9-BBN is 9-borabicyclo[3.3.1]nonane,

LAH is lithium aluminum hydride,

TsCI is tosylchloride,

AcSK is potassium thioacetate,

mCPBA is methachloroperbenzoic acid,

cbz is benzyloxycarbonyl,

L^(c) is L^(aa), L^(bb) or C1-6 alkylene,

E^(c) is C1-6 alkylene,

G¹ is --O--, --S--, --SO--, or --SO₂ --,

G² is --NR⁴ --,

Bu₄ NBr is tetrabutylammonium bromide,

Py is pyridine,

R^(d) is

1) acetyl or hydrogen when G³ is --S--,

2) hydrogen when G³ is --O-- or --NR^(4a) in which R^(4a) is C1-4 alkyl,

3) NH-protecting group as defined hereinbefore when G³ is --NH--

Z is NH-protecting group as defined hereinbefore and

Ph^(a) is phenyl may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy,halogen, nitro or trifluoromethyl.

The compounds of the formula (II-a) are a part of the compounds of theformula (VI).

The compounds of the formula (II-b) are a part of the compounds of theformula (VIII). The compounds of the formula (IV), (V-O) or (VI) asstarting materials may be prepared by the known methods. For example,these compounds may be prepared by the methods described in Example inthe present specification.

In each reaction in the present specification, obtained products may bepurified by conventional techniques. For example, purification may becarried out by distillation at atmospheric or reduced pressure, by highperformance liquid chromatography, by thin layer chromatography or bycolumn chromatography using silica gel or magnesium silicate, by washingor by recrystallization. Purification may be carried out after eachreaction, or after a series of reactions.

The other starting materials and reagents in the present invention areknown per se or may be prepared by known methods. ##STR201##

INDUSTRIAL AVAILABILITY

Pharmacological Activities

The compounds of the present invention of the formula (I) are useful asPGE₂ antagonists or agonists, because they can bind onto prostaglandinE₂ receptors and have antagonist or agonist activity against the actionthereof.

As mentioned hereinbefore, to antagonize PGE₂ receptor is linked toinhibit diuretic, to inhibit hyperlipemia, to inhibit reduce of bloodsugar, to inhibit uterine contraction, to have analgesic action, toinhibit digestive peristalsis, to induce sleep. Therefor, PGE₂antagonists are considered to be useful as anti-hyperlipemia, for theprevention of abortion, for analgesics, or as antidiarrheals or sleepinducer.

As mentioned hereinbefore, to agonize for PGE₂ receptor is liked topromote diuretic, to promote hyperlipemia, to promote reduce of bloodsugar, to contractile uterine, to promote digestive peristalsis, tosuppress gastric acid secretion or to reduce blood pressure. Therefor,PGE₂ receptor agonists are considered to be useful for diuretic,anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis orantihypertensive.

For example, in standard laboratory test, the effects of the compoundsof the present invention were confirmed by inhibitory effect on bindingPGE₂ using expression cell of receptor.

(I) Binding assay using expression cell of prostanoide receptor subtype

The preparation of membrane fraction was carried out according to themethod of Sugimoto et al (J. Biol. Chem. 267, 6463-6466 (1992)), usingexpression CHO cell of prostanoide receptor subtype (mouse EP₃ α).

The standard assay mixture contained membrane fraction (0.5 mg/ml), [³H]-PGE₂ in a final volume of 200 ml was incubated for 1hour at roomtemperature. The reaction was terminated by addition of 3 ml of ice-coldbuffer. The mixture was rapidly filtered through a glass filter (GF/B).The radioactivity associated with the filter was measured by liquidscintillation counting.

Kd and Bmax values were determined from Scatchard plots (Ann. N.Y. Acad.Sci., 51, 660 (1949)). Non-specific binding was calculated as the bondin the presence of an excess (2.5 nM) of unlabeled PGE₂. In theexperiment for competition of specific [³ H]-PGE₂ binding by thecompounds of the present invention, [³ H]-PGE₂ was added at aconcentration of 2.5 nM and the compounds of the present invention wereat a concentration of 1mM. Buffer: 10 mM potassium phosphate (pH6.0), 1mM EDTA, 10 mM MgCl₂, 0.1M NaCl.

The dissociation constant Ki (μM) of each compound was calculated by thefollowing equation.

    Ki=IC50/(1+([C]/Kd))

The results were shown as follows.

    ______________________________________                                                     dissociation constant                                              Example No. ki (μM)                                                      ______________________________________                                        3            0.048                                                              3 (2) 0.0099                                                                  3 (6) 0.15                                                                    3 (8) 2.0                                                                     5 0.080                                                                       5 (1) 0.0086                                                                ______________________________________                                    

Toxicity

The toxicity of the compounds of the present invention are very low andtherefore, it is confirmed that these compounds are safe for use asmedicine.

Application for Pharmaceuticals

The compounds of the formula (I) of the present invention are useful forPGE₂ antagonists or agonists, because they can bind onto PGE₂ receptorsand have an activity to antagonize or agonize for the action thereof.

As mentioned hereinbefore, to antagonize PGE₂ is linked to inhibithyperlipemia, to inhibit uterine contraction, to have analgesic action,to inhibit digestive peristalsis or to induce sleep. Therefor, PGE₂antagonists are considered to be useful as anti-hyperlipemia, for theprevention of abortion, for analgesics, or as antidiarrheals or sleepinducer.

As mentioned hereinbefore, to agonize PGE₂ is linked to promotediuretic, to promote reduce of blood sugar, to contractile uterine, topromote digestive peristalsis, to suppress gastric acid secretion or toreduce blood pressure. Therefor, PGE₂ agonists are useful for diuretics,anti-diabete abortient, cathartics, antiulcer, anti-gastritis orantihypertensive.

For the purpose above described, the compounds of the formula (I),non-toxic salts thereof and hydrates thereof may be normallyadministered systematically or partially, usually by oral or parenteraladministration.

The doses to be administered are determined depending upon age, bodyweight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment etc. In the humanadult, the doses per person per dose are generally between 1 μg and 100mg, by oral administration, up to several times per day, and between 0.1μg and 10 mg, by parenteral administration (preferred into vein) up toseveral times per day, or continuous administration between 1and 24hours per day into vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

On administration of the compounds of the present invention, it is usedas solid compositions, liquid compositions or other compositions fororal administration, as injections, liniments or suppositories etc. forparenteral administration.

Solid compositions for oral administration include compressed tablets,pills, capsules, dispersible powders, and granules etc.

Capsules contain hard capsules and soft capsules.

In such solid compositions, one or more of the active compound(s) is orare, admixed with at least one inert diluent such as lactose, mannitol,mannit, glucose, hydroxypropyl cellulose, microcrystalline cellulose,starch, polyvinylpyrrolidone, magnesium metasilicate aluminate. Thecompositions may also comprise, as is normal practice, additionalsubstances other than inert diluents: e.g. lubricating agents such asmagnesium stearate, disintegrating agents such as cellulose calciumglycolate, and assisting agents for dissolving such as glutamic acid orasparaginic acid. The tablets or pills may, if desired, be coated withfilm of gastric or enteric material such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropyl cellulose phthalate etc., or becoated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Liquid compositions for oral administration includepharmaceutically-acceptable emulsions, solutions, syrups and elixirsetc. In such liquid compositions, one or more of the active cornpound(s)is or are comprised in inert diluent(s) commonly used in the art (forexample, purified water, ethanol etc.). Besides inert diluents, suchcompositions may also comprise adjuvants such as wetting agents,suspending agents, sweetening agents, flavouring agents, perfumingagents and preserving agents.

Other compositions for oral administration include spray compositionswhich may be prepared by known methods and which comprise one or more ofthe active compound(s). Spray compositions may comprise additionalsubstances other than inert diluents: e.g. stabilizing agents such assodium hydrogen sulfate, stabilizing agents to give the title compoundisotonicity, isotonic buffer such as sodium chloride, sodium citrate,citric acid. For preparation of such spray compositions, for example,the method described in the U.S. Pat. Nos. 2,868,691 or 3,095,355 may beused.

Injections for parenteral administration include sterile aqueous ornon-aqueous solutions, suspensions and emulsions. Aqueous solutions orsuspensions include distilled water for injection and physiological saltsolution. Non-aqueous solutions or suspensions include propylene glycol,polyethylene glycol, plant oil such as olive oil, alcohol such asethanol, POLYSORBATE80 (registered trade mark) etc. Such compositionsmay comprise additional diluents: e.g. preserving agents, wettingagents, emulsifying agents, dispersing agents, stabilizing agent,assisting agents such as assisting agents for dissolving (for example,glutamic acid, asparaginic acid). They may be sterilized for example, byfiltration through a bacteria-retaining filter, by incorporation ofsterilizing agents in the compositions or by irradiation. They also bemanufactured in the form of sterile solid compositions and which can bedissolved in sterile water or some other sterile diluents for injectionimmediately before used.

Other compositions for parenteral administration include liquids forexternal use, and endemic liniments, ointment, suppositories andpessaries which comprise one or more of the active compound(s) and maybe prepared by know methods.

Best mode to practice the invention

The following reference examples and examples are intended toillustrate, but not limit, the present invention. The solvents inparentheses show the developing or eluting solvents and the ratios ofthe solvents used are by volume in chromatographic separations. Thesymbol in the structure is the same meaning as defined hereinbefore.

REFERENCE EXAMPLE 1 ##STR202##

To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (50 g) andpyridine (50 ml) in methylene chloride (200 ml), tosylchloride (76.3 g)in methylene chloride (150 ml) was added dropwise at -20° C. The mixturewas stirred for 1 hour at room temperature. The reaction mixture wasadded to 2N aqueous solution of hydrochloric acid (300 ml) and extractedby ethyl acetate. The organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried over with anhydrousmagnesium sulfate and concentrated. The residue was purified on silicagel column chromatography (hexane: AcOEt=3:1) to give the title compound(95.8 g) having the following physical data.

TLC: Rf 0.21(hexane: AcOEt=3:1);

MS (El): m/z 271(M⁺ --CH₃).

REFERENCE EXAMPLE 2 ##STR203##

A suspension of sodium hydride (1.47 g) in dimethylformamide (DMF) (20ml) was cooled to 0° C. The solution of phenol (3.45 g) in DMF (20 ml)was added dropwise to the suspension. The mixture was stirred for 1hourat room temperature. To the mixture, the solution of the compoundprepared in Reference Example 1(10 g) in DMF (20 ml) was added. Themixture was stirred for 2 hours at 80° C. The reaction mixture wascooled to room temperature, poured into iced water and extracted withether two times. The organic layer was washed with water and a saturatedaqueous solution of sodium chloride, dried over with anhydrous magnesiumsulfate and concentrated. The residue was purified on silica gel columnchromatography (hexane: AcOEt=9:1) to give the title compound (6.53 g)having the following physical data.

TLC:Rf 0.22 (hexane: AcOEt=9:1);

MS (El): m/z 208 (M⁺), 193.

REFERENCE EXAMPLE 3 ##STR204##

To a solution of the compound prepared in Reference Example 2 (6.37 g)in methanol (30 ml), 2N aqueous solution of hydrochloric acid (3 ml) wasadded. The mixture was refluxed for 2 hours. The reaction mixture wascooled to room temperature, diluted with ethyl acetate and washed withsaturated aqueous solution of sodium hydrogen carbonate. The organiclayer was dried over with anhydrous magnesium sulfate and concentratedto give the title compound (5.14 g) having the following physical data.

TLC:Rf 0.40 (AcOEt);

MS (El) m/z 168 (M⁺).

REFERENCE EXAMPLE 4 ##STR205##

To a solution of the compound prepared in Reference Example 3 (3.5 g) inpyridine (10 ml), the solution of tosylchloride (8 g) in methylenechloride (10 ml) was added at -20° C. The mixture was stirred for 1hourat room temperature. The reaction mixture was poured into 2N aqueoussolution of hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over with anhydrous magnesium sulfate andconcentrated. The residue was purified on silica gel columnchromatography (AcOEt: CH₂ Cl₂ =1:49) to give the title compound (4.96g) having the following physical data.

TLC:Rf 0.31(hexane:AcOEt=3:2);

MS (El): m/z 322 (M⁺).

REFERENCE EXAMPLE 5 ##STR206##

To a solution of the compound prepared in Reference Example 4 (9.88 g)and pyridium p-toluene sulfate (100 mg) in methylene chloride (60 ml),dihydropyran (5.58 ml) was added dropwise at 0° C. The mixture wasstirred for 6 hours at room temperature. Triethylamine (0.2 ml) wasadded to the mixture. The solvent was distilled off. The residue waspurified on silica gel column chromatography (hexane: AcOEt=41:9) togive the title compound (11.79 g) having the following physical data.

TLC: Rf 0.28 (hexane: AcOEt=4:1);

MS (El):m/z 406 (M⁺).

REFERENCE EXAMPLE 6 ##STR207##

By using (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol instead of2,2-dimethyl-1,3-dioxolane-4-methanol as starting material, the titlecompound having the following physical data was obtained by the sameprocedure as Reference Example 1→Reference Example 2→Reference Example3→Reference Example 4→Reference Example 5.

TLC: Rf 0.28 (hexane: AcOEt=4:1);

MS (El): m/z 406 (M⁺).

REFERENCE EXAMPLE 6(1) ##STR208##

By using (R)-(-)-2,2-dimethyl-1,3-dioxolane-4-methanol instead of2,2-dimethyl-1,3-dioxolane-4-methanol as starting material, the titlecompound having the following physical data was obtained by the sameprocedure as Reference Example 6.

TLC:Rf 0.28(hexane:AcOEt=4:1);

MS (El): m/z 406 (M⁺).

REFERENCE EXAMPLE 7 ##STR209##

To a solution of 1-phenyl-1,2-ethandiol (13.82 g) in pyridine (50 ml),tosylchloride (21g) was added for 30 minutes at -20° C. The reactionmixture was stirred for 30 minutes at -20° C. and, succeedingly, stirredfor 16 hours at room temperature. The reaction mixture was poured intoiced water and extracted with ether. The organic layer was washed with2N aqueous solution of hydrochloric acid, water and saturated aqueoussolution of sodium hydrogen carbonate, succeedingly, dried over withanhydrous sodium sulphate and concentrated. The residue was purified onsilica gel column chromatography (hexane:AcOEt=3:1) to give the titlecompound (18.56 g) having the following physical data.

TLC:Rf 0.41(hexane: AcOEt=2:1);

MS (El):m/z 292 (M⁺).

REFERENCE EXAMPLE 8 ##STR210##

To a solution of compound prepared in Reference Example 7 (10 g) inmethylene chloride (100 ml), dihydropyran (5.76 g) was added dropwise atroom temperature. P-toluene sulfonic acid (catalytic amount) was addedto the mixture. The mixture was stirred overnight at room temperature.To the reaction mixture, triethylamine (two drops) was added. Themixture was concentrated. The reside was dissolved in ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over with anhydrous sodium sulfate andconcentrated to give the title compound (12.9 g) having the followingphysical data.

TLC: Rf 0.50 (hexane AcOEt=2:1);

MS (El) m/z 376 (M⁺).

REFERENCE EXAMPLE 9 ##STR211##

To a solution of 5-methoxy-1-tetralone (100 g) in methylene chloride(500 ml), trimethylsilylcyanide (88 ml) and zinc iodide (3 g) was added.The mixture was stirred overnight at room temperature. To the reactionsolution, water was added. The mixture was extracted with mixturesolvent (AcOEt : hexane=1: 1) two times. The organic layer was washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate and concentrated. The residue wasdissolved in pyridine (370 ml). Phosphorous oxychloride (POCl₃) (133 ml)was added dropwise to the solution. The reaction mixture was refluxedfor 3 hours and cooled to room temperature. The reaction mixture waspoured into iced water and extracted with ethyl acetate two times. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over anhydrous sodium sulfate and concentrated.The residue was purified on silica gel column chromatography (AcOEt: CH₂Cl₂ =1:19), and succeedingly, recrystalized from solvent of AcOEt-hexaneto give the title compound (72 g) having the following physical data.

TLC: Rf 0.43 (hexane: AcOEt=3:1);

MS (El) :m/z 185 (M⁺).

REFERENCE EXAMPLE 10 ##STR212##

A mixture of compound prepared in Reference Example 9 (60 g),2,3-dichloro-5,6-dicyano-1,4-benzoquinon (DDQ) (81g) and benzene (700ml) was refluxed for 6 hours. The reaction mixture was cooled to roomtemperature. To a reaction solution, mixture solvent (AcOEt:hexane=1:1)(500 ml) was added. The mixture was filtrated. The precipitate waswashed with mixture solvent (AcOEt:hexane=1:1). The filtrate was washedwith saturated aqueous solution of sodium hydrogen carbonate four times,dried over with anhydrous sodium sulfate and concentrated. The residewas recrystalized from AcOEt-hexane to give the title compound (56.6 g)having the following physical data.

TLC: Rf 0.42 (hexane: AcOEt=3:1);

MS (El): m/z 183 (M⁺)

m.p. 132-133° C.

REFERENCE EXAMPLE 11 ##STR213##

To a solution of compound prepared in Reference Example 10 (91.6 g) inmethylene chloride (500 ml), a solution of boron triburomide (104 ml) inmethylene chloride (100 ml) was added dropwise at 0° C. The mixture wasstirred for 20 hours at room temperature. The reaction mixture waspoured into iced water and extracted with ethyl acetate two times. Theorganic layer was washed with aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, driedover with anhydrous magnesium sulfate and concentrated to give the titlecompound (84.4 g) having the following physical data.

TLC:Rf 0.32 (hexane:AcOEt=2:1);

MS (El): m/z 169 (M⁺);

m.p. 198-201° C.

REFERENCE EXAMPLE 12 ##STR214##

To a solution of compound prepared in Reference Example 11(82.5 g) inmethylene chloride (1000 ml), diisopropylethylamine (102 ml) andmethyoxymethylchloride (41ml) were added at 0° C. The mixture wasstirred overnight at room temperature. The solvent was distilled off.The residue was diluted with mixture solvent (AcOEt: hexane=1:1), washedwith water, aqueous solution of hydrochloric acid, saturated aqueoussolution of sodium hydrogen carbonate and a saturated aqueous solutionof sodium chloride succeedingly, dried over with anhydrous magnesiumsulfate and concentrated. The residue was recrystallized from themixture solvent (AcOEt: hexane=1:10) to give the title compound (88.8 g)having the following physical data.

TLC:Rf 0.34(hexane:AcOEt=4:1);

MS (El) :m/z 213 (M⁺).

REFERENCE EXAMPLE 13 ##STR215##

To a solution of compound prepared in Reference Example 12 (95.5 g) intoluene (750 ml), diisobutyl aluminum hydride (324 ml, 1.5 mol/toluenesolution) was added at -50° C. The mixture was heated to 0° C. for 2hours. The reaction mixture was cooled to -30° C. Methanol (30 ml) wasadded to the mixture. The reaction solution was heated to -5° C. Anaqueous solution of sodium sulfate was added to the mixture. Theprecipitate was filtrated. The filtrate was concentrated. The residuewas dissolved in tetrahydrofuran (THF)-AcOEt (100 ml-400 ml). 2N aqueoussolution of hydrochloric acid (250 ml) was added to the solution. Themixture was stirred for 30 minutes. The organic layer was isolated. Theaqueous layer was extracted with ethyl acetate. The organic layer waswashed with an aqueous solution of sodium hydrogen carbonate and asaturated aqueous solution of sodium chloride, dried over with anhydrousmagnesium sulfate and concentrated. To the residue, hexane (600 ml) wasadded. The mixture was laid for 2 days. The crystal was collected byfiltration to give the title compound (70.6 g) having the followingphysical data. In addition, the mother liquor was purified on silica gelcolumn chromatography (hexane: AcOEt=7:1) to give the title compound(20.9 g) having the following physical data.

TLC:Rf 0.33(hexane:AcOEt=3:1);

MS (El): m/z 216 (M⁺).

REFERENCE EXAMPLE 14 ##STR216##

A mixture of sodium hydride (4.66 g) and dimethylsulfoxide (DMSO) (100ml) was stirred for 50 minutes at 80° C. The reaction mixture was cooledto room temperature. A solution of methyltriphenylphosphnium bromide(41.6 g) in DMSO (120 ml) was added dropwise to the reaction mixture inorder to adjust reaction temperature to 20-30° C. The mixture wasstirred for 30 minutes at room temperature. To the reaction solution, asolution of compound prepared in Reference Example 13 (15.56 g) in DMSO(80 ml) was added dropwise. The mixture was stirred for 15 minutes atroom temperature. The reaction mixture was poured into iced water,extracted with mixture solvent (AcOEt: hexane=1:2) three times. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over with anhydrous magnesium sulfate andconcentrated. To the residue, mixture solvent (ether:hexane=1:4) (200ml) was added. The mixture was filtrated. The filtrate was concentrated.The residue was purified on silica gel column chromatography(hexane:AcOEt=6:1) to give the title compound (14.2 g) having thefollowing physical data.

TLC: Rf 0.52 (hexane: AcOEt=4:1);

MS (El):mlz 214 (M⁺).

REFEFENCE EXAMPLE 15 ##STR217##

To a solution of compound prepared in Reference Example 14 (14.2 g) inTHF (60 ml), 9-borabicyclo[3.3.1]nonane (9-BBN) (172 ml, 0.5 mol/l THFsolution) was added dropwise under an atmosphere of Argon gas at roomtemperature. The mixture was stirred for 2.5 hours at room temperature.To the reaction solution, ethanol (30 ml) was added dropwise. Inaddition, to the mixture, 5N-aqueous solution of sodium hydroxide (50ml) was added. An aqueous solution of hydrogen peroxide (50 ml) wasadded dropwise to the mixture in order to adjust reaction temperature to50-60° C. The reaction mixture was stirred for 30 minutes, poured intoiced water and extracted with ethyl acetate two times. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over with anhydrous magnesium sulfate and concentrated.The residue was purified on silica gel column chromatography(hexane:AcOEt=7:3) to give the title compound (14.81 g) having thefollowing physical data.

TLC: Rf 0.38 (hexane:AcOEt=7:3);

MS (El): m/z 232 (M⁻), 202.

REFERENCE EXAMPLE 16 ##STR218##

To a solution of compound prepared in Reference Example 13 (5.3 g) inmethanol (40 ml), sodium boron hydride (910 mg) was added. The mixturewas stirred for 1hour at room temperature. The solvent was distilledoff. Water was added to the reside. The mixture was extracted with ethylacetate. The organic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over with anhydrous magnesium sulfateand concentrated to give the title compound (5.21g) having the followingphysical data.

TLC: Rf 0.33 (hexane: AcOEt=2:1);

MS (El) :m/z 218 (M⁺).

REFERENCE EXAMPLE 17 ##STR219##

To a solution of compound prepared in Reference Example 13 (3.11 g) inchloroform (30 ml), carbomethoxymethylene triphenylphosphorane (98% 5.88g) was added. The mixture was stirred for 16 hours at room temperature.The reaction mixture was concentrated. Ether was added to the residue.The precipitate was filtrated. The filtrate was concentrated. Theresidue was dissolved in hexane. The precipitate was filtrated. Thefiltrate was concentrated to give the title compound (3.92 g) having thefollowing physical data.

TLC: RF 0.50 (hexane: AcOEt=5:1);

MS (El): m/z 272 (M⁺).

REFERENCE EXAMPLE 18 ##STR220##

To a solution of compound prepared in Reference Example 17 (3.81 g) inethyl acetate (70 ml), 10% Pd-C (380 mg) was added. The mixture wasstirred under an atmosphere of H₂ gas for 1hour. The reaction solutionwas filtrated. The filtrate was concentrated to give the title compound(3.69 g) having the following physical data.

TLC Rf 0.48 (hexane AcOEt=5:1);

MS (El): m/z 274 (M⁺).

REFERENCE EXAMPLE 19 ##STR221##

To a suspension of lithium aluminum hydride (2.91g) in THF (50 ml), aSolution of compound prepared in Reference Example 18 (12.5 g) in THF(150 ml) was added dropwise at room temperature. The mixture was stirredfor 1 hour at room temperature. A small amount of ethyl acetate wasadded to the reaction mixture. A saturated aqueous solution of anhydroussodium sulfate was added to the mixture. The white precipitate wasfiltrated by Celite (Registered trade mark). The filtrate wasconcentrated to give the title compound (11.35 g) having the followingphysical data.

TLC:Rf 0.27(hexane:AcOEt=2:1);

MS (El):m/z 246 (M⁺).

REFERENCE EXAMPLE 20 ##STR222##

6-Hydroxy-2-naphthalene sulfonic acid sodium salt (18 g) was dissolvedin 2N aqueous solution of sodium hydroxide (36.6 ml) with heating. THF(70 ml) was added to the solution. Ethylchloroformate (7 ml) was addeddropwise to the mixture under cooling with ice. The mixture was stirredfor 3 hours at room temperature. The white crystal was filtrated, washedwith water and THF and dried over under reduced pressure to give thetitle compound (16.3 g) having the following physical data.

TLC: Rf 0.09 (CHCl₃ :MeOH=5:1)

MS (El): m/z 318 (M⁺).

REFERENCE EXAMPLE 21 ##STR223##

The solution of compound prepared in Reference Example 15 (7.63 g) inpyridine (20 ml) was cooled to -30° C. Tosylchloride (8.75 g) was addedto the solution. The mixture was stirred for 2 hours at roomtemperature. The reaction mixture was cooled to 0° C. Water (1 ml) wasadded to the mixture. The mixture was stirred for 20 minutes at roomtemperature. The reaction solution was poured into AcOEt-2N-aqueoussolution of hydrochloric acid (2:1, 400 ml). The organic layer wasisolated, washed with water and saturated aqueous solution of sodiumhydrogen carbonate, dried over with anhydrous magnesium sulfate andconcentrated. The residue was dissolved in acetone (100 ml). Potassiumthioacetate (5.62 g) was added to solution. The mixture was refluxed for2 hours. The reaction mixture was cooled to room temperature, pouredinto water and extracted with mixture solvent (AcOEt: hexane=1:2) twotimes. The organic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over with anhydrous magnesium sulfateand concentrated to give the title compound (9.28 g) having thefollowing physical data.

TLC: Rf 0.55 (hexane:AcOEt=7:3);

MS (El):m/z 290 (M⁺).

REFERENCE EXAMPLE 21(1) ##STR224##

By using compound prepared in Reference Example 16, the title compoundhaving the following physical data was obtained by the same procedure ofReference Example 21.

TLC:Rf 0.40 (hexane:AcOEt=4:1);

MS (El): m/z 276 (M⁺).

REFERENCE EXAMPLE 21(2) ##STR225##

By using compound prepared in Reference Example 19, the title compoundhaving the following physical data was obtained by the same procedure ofReference Example 21.

TLC: Rf 0.57 (hexane: AcOEt=7:3);

MS (El):m/z 304 (M⁺).

REFERENCE EXAMPLE 22 ##STR226##

To a solution compound prepared in Reference Example 20 (16.3 g) in DMF(150 ml), thionylchloride (18.7 ml) was added dropwise for 1.5 hours at0° C. The mixture was stirred for 2.5 hours at room temperature. Thereaction mixture was poured into iced water. The white crystal wasfiltrated, washed with water and dried over under reduced pressure togive the title compound (13.4 g) having the following physical data.

TLC: Rf 0.72 (hexane: AcOEt=1:1);

MS (El) :m/z 314 (M⁺).

REFERENCE EXAMPLE 23 ##STR227##

The compound prepared in Reference Example 22 (13.5 g) was dissolved inmixture solvent of water (90 ml), conc. sulfuric acid (18 ml) and THF(100 ml). A powder of zinc (13.9 g) was added to the solution at 0° C.The mixture was stirred overnight at room temperature. The reactionsolution was filtrated. The filtrate was distilled off under reducedpressure. The residual aqueous solution was extracted with ethylacetate. The organic layer was dried over with anhydrous magnesiumsulfate, and concentrated. The residue was purified on silica gel columnchromatography (hexane : AcOEt=1:1) to give the title compound (9.4 g)having the following physical data.

TLC: Rf 0.22 (hexane: AcOEt=1:1);

MS (El):m/z 248 (M⁺).

REFERENCE EXAMPLE 24 ##STR228##

To a solution of the compound prepared in Reference Example 21(4.5 g)and the compound prepared in Reference Example 5 (6.3 g) in ethanol (30ml), sodium ethoxide (1.4 g) was added at 0° C. The mixture was stirredfor 1 hour at room temperature. The reaction mixture was poured intoiced water and extracted with ethyl acetate two times. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride, dried over with anhydrous magnesium sulfate and concentrated.The residue was purified on silica gel column chromatography (hexane:AcOEt=6:1) to give the title compound (6.75 g) having the followingphysical data.

TLC: Rf 0.32 (hexane: AcOEt=5:1)

MS (El):m/z 482 (M⁺).

REFERENCE EXAMPLE 24(1) ##STR229##

By using the compound prepared in Reference Example 21 and the compoundprepared in Reference Example 6, the title compound having the followingphysical data by the same procedure of Reference Example 24.

TLC: Rf 0.32 (hexane: AcOEt=5:1)

MS (El): m/z 482 (M⁺).

REFERENCE EXAMPLE 24(2) ##STR230##

By using the compound prepared in Reference Example 21 and the compoundprepared in Reference Example 6(1), the title compound having thefollowing physical data by the same procedure of Reference Example 24.

TLC: Rf 0.32 (hexane: AcOEt=5:1)

MS (El): m/z 482 (M⁺)

REFERENCE EXAMPLE 24(3) ##STR231##

By using the compound prepared in Reference Example 21(1) and thecompound prepared in Reference Example 5 the title compound having thefollowing physical data by the same procedure of Reference Example 24.

TLC: Rf 0.32 (hexane: AcOEt=4:1);

MS (El): m/z 468 (M⁺).

REFERENCE EXAMPLE 25 ##STR232##

To a solution of the compound prepared in Reference Example 21(2) (61mg) and the compound prepared in Reference Example 8 (75 mg) in ethanol(4 ml), sodium ethoxide (28 mg) was added. The mixture was stirred for 1hour at room temperature. The reaction mixture was concentrated. Waterwas added to the residue. The mixture was extracted with ethyl acetate.The organic layer was washed with water and a saturated aqueous solutionof sodium chloride, dried over with anhydrous sodium sulfate andconcentrated. The residue was purified on silica gel columnchromatography (hexane: AcOEt=5:1) to give the title compound (68 mg)having the following physical data.

TLC: Rf 0.65 (hexane AcOEt=5:1);

MS (El): m/z 466 (M⁺).

REFERENCE EXAMPLE 26 ##STR233##

To a solution of sodium hydride (400 mg) in DMF (30 ml), the compoundprepared in Reference Example 23 (2.48 g) was added under an atmosphereof Argon gas. The mixture was stirred for 30 minutes at roomtemperature. A solution of the compound prepared in Reference Example 5(4.06 g) in DMF (5 ml) was added dropwise to the reaction solution at 0°C. The mixture was stirred for 6 hours at room temperature. Water (30ml) was added to the reaction solution. The mixture was extracted withethyl acetate. The organic layer was dried over with anhydrous magnesiumsulfate and concentrated. The residue was purified on silica gel columnchromatography (hexane: AcOEt=2:1) to give the title compound (3.44 g)having the following physical data.

TLC: Rf 0.49 (hexane: AcOEt=5:1);

MS (El): m/z 482 (M⁺).

REFERENCE EXAMPLE 27 ##STR234##

To a suspension of the compound prepared in Reference Example 24(3) (466mg) and sodium hydrogen carbonate (170 mg) in methylene chloride (2 ml),70% mCPBA (245 mg) was added at 0° C. The mixture was stirred for 1 hourat 0° C. Water was added to the reaction mixture. The mixture wasextracted with ether. The organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried over with anhydrousmagnesium sulfate and concentrated. The residue was purified on silicagel column chromatography (hexane: AcOEt=1:4) to give the title compound(324 mg) having the following physical data.

TLC: Rf 0.12 (hexane: AcOEt=1:1);

MS (El): m/z 468 (M⁺ --O).

REFERENCE EXAMPLE 27(1) ##STR235##

By using the compound prepared in Reference Example 24, the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 27.

TLO: Rf 0.44 (hexan e AcOEt=1:1);

MS (El): m/z 498 (M⁺).

REFERENCE EXAMPLE 27(2) ##STR236##

By using the compound prepared in Reference Example 25, the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 27.

TLC: Rf 0.61 (AcOEt);

MS (El): m/z 482 (M⁺).

REFERENCE EXAMPLE 27(3) ##STR237##

By using the compound prepared in Reference Example 26, the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 27.

TLC: Rf 0.33(hexane: AcOEt=1:1);

MS (El): m/z 498 (M⁺).

REFERENCE EXAMPLE 28 ##STR238##

To a suspension of the compound prepared in Reference Example 24(3) (466mg) and sodium hydrogen carbonate (340 mg) in methylene chloride (3 ml),70% mCPBA (735 mg) was added at 0° C. The mixture was stirred for 2hours at 0° C. Water was added to the reaction mixture. The mixture wasextracted with ether. The organic layer was washed with water and asaturated aqueous solution of sodium chloride, dried over with anhydrousmagnesium sulfate and Concentrated. The residue was purified on silicagel column chromatography (hexane: AcOEt=2:1) to give the title compound(300 mg) having the following physical data.

TLC: Rf 0.37 (hexane: AcOEt=1:1);

MS (El): m/z 500 (M⁺).

REFERENCE EXAMPLE 28(1) ##STR239##

By using the compound prepared in Reference Example 24, the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 28.

TLC: Rf 0.49 (hexane: AcOEt=1:1);

MS (El): m/z 514 (M⁺).

REFERENCE EXAMPLE 28(2) ##STR240##

By using the compound prepared in Reference Example 25, the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 28.

TLC: Rf 0.27 (hexane: AcOEt=5:1);

MS (El): m/z 498 (M⁺).

REFERENCE EXAMPLE 28(3) ##STR241##

By using the compound prepared in Reference Example 26, the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 28.

TLC: Rf 0.35 (hexane :AcOEt=1:1);

MS (El): m/z 514 (M⁺).

REFERENCE EXAMPLE 29 ##STR242##

To a solution of potassium hydroxide (62 mg) in methanol (10 ml), thecompound prepared in Reference Example 26 (446 mg) was added at roomtemperature. The mixture was stirred overnight at room temperature. 2Naqueous solution of hydrochloric acid was added to the reaction mixturein order to adjust to pH 7 at 0° C. The mixture was extracted with ethylacetate. The organic layer was washed with water and a saturated aqueoussolution of sodium chloride, dried over with anhydrous magnesium sulfateand concentrated, The white crystal was washed with ether to give thetitle compound (341 mg) having the following physical data.

TLC: Rf 0.34 (hexane: AcOEt=5:1);

MS (El): m/z 410 (M⁺).

REFERENCE EXAMPLE 29(1) ##STR243##

By using the compound prepared in Reference Example 27(3), the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 29.

TLC: Rf 0.31 (hexane: AcOEt=1:1);

MS (El) m/z 426 (M⁺).

REFERENCE EXAMPLE 29(2) ##STR244##

By using the compound prepared in Reference Example 28(3), the titlecompound having the following physical data was obtained by the sameprocedure of Reference Example 29.

TLC: Rf 0.32 (hexane: AcOEt=1:1);

MS (El): m/z 442 (M⁺).

EXAMPLE 1

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2RS-propanol ##STR245##

To a solution of the compound prepared in Reference Example 24 (482 mg)in mixture solvent of AcOEt-methanol (3 ml-2 ml), 4N aqueous solution ofhydrochloric acid (3 ml, solution of ethyl acetate) was added. Themixture was stirred for 2 hours at room temperature. The reactionsolution was concentrated. The residue was diluted with ethyl acetate,washed with water and a saturated aqueous solution of sodium chloride,dried over with anhydrous magnesium sulfate and concentrated. Theresidue was purified on silica gel column chromatography (hexane:AcOEt=7:3) to give the present invention compound (320 mg) having thefollowing physical data.

TLC: Rf 0.42 (hexane: AcOEt=2:1);

MS (APCl): m/z 353 (M⁺ -1), 169, 156;

NMR (CDCl₃): δ 8.15-8.08 (1H, m), 7.59 (1H, d, J=8.6 Hz), 7.45-7.23 (5H,m), 7.02-6.80 (4H, m), 5.35 (1 H, s), 4.16-3.98 (3H, m), 3.40-3.30 (2H,m), 3.01-2.68 (5H, m).

EXAMPLE 1(1)

1-[2-(5-hydroxy-1-naphthyl)ethylsulfinyl]-3-phenoxy-2RS-propanol##STR246##

By using the compound prepared in Reference Example 27(1), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.23 (hexane: AcOEt=1:1);

MS (El): m/z 370 (M⁺).

EXAMPLE 1(2)

1-[2-(5-hydroxy-1-naphthyl)ethylsulfonyl]-3-phenoxy-2RS-propanol##STR247##

By using the compound prepared in Reference Example 28(1), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.26 (hexane: AcOEt=1:1);

MS (El): m/z 386 (M⁺).

EXAMPLE 1(3)

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2R-propanol ##STR248##

By using the compound prepared in Reference Example 24(1), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.42 (hexane: AcOEt=2:1);

MS (APCl): m/z 353 (M⁺ -1), 169, 156.

EXAMPLE 1(4)

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenoxy-2S-propanol ##STR249##

By using the compound prepared in Reference Example 24(2), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.42 (hexane AcOEt=2:1);

MS (APCl) m/z 353 (M⁺ -1), 169, 156.

EXAMPLE 1(5)

1-(5-hydroxy-1-naphthyl)methylthio-3-phenoxy-2RS-propanol ##STR250##

By using the compound prepared in Reference Example 24(3), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.40 (hexane: AcOEt=1:1);

MS (El): m/z 340 (M⁺).

EXAMPLE 1(6)

1-(5-hydroxy-1-naphthyl)methylsulfinyl-3-phenoxy-2RS-propanol ##STR251##

By using the compound prepared in Reference Example 27, the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.42 (AcOEt);

MS (El) m/z 356 (M⁺).

EXAMPLE 1(7)

1-(5-hydroxy-1-naphthyl)methylsulfonyl-3-phenoxy-2RS-propanol ##STR252##

By using the compound prepared in Reference Example 28, the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.24 (hexane: AcOEt=1:1);

MS (El): m/z 372 (M⁺).

EXAMPLE 1(8)

2-[3-(5-hydroxy-1-naphthyl)propylthio]-1-phenyl-1RS-ethanol ##STR253##

By using the compound prepared in Reference Example 25, the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.33 (hexane: AcOEt=2:1);

MS (El) m/z 338 (M⁺).

EXAMPLE 1(9)

2-[3-(5-hydroxy-1-naphthyl)propylsulfinyl]-1-phenyl-1RS-ethanol##STR254##

By using the compound prepared in Reference Example 27(2), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.34 (AcOEt);

MS (El): m/z 354 (M⁺)

EXAMPLE 1(10)

2-[3-(5-hydroxy-1-naphthyl)propylsulfonyl]-1-phenyl-1RS-ethanol##STR255##

By using the compound prepared in Reference Example 28(2), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.10 (hexane : AcOEt=2:1);

MS (El) m/z 370 (M⁺).

EXAMPLE 1(11)

1-(5-hydroxy-1-naphthyl)thio-3-phenoxy-2RS-propanol ##STR256##

By using the compound prepared in Reference Example 29, the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.40 (hexane: AcOEt=1:1);

MS (El): m/z 326 (M⁺).

EXAMPLE 1(12)

1-(5-hydroxy-1-naphthyl)sulfinyl-3-phenoxy-2RS-propanol ##STR257##

By using the compound prepared in Reference Example 29(1), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.24 (hexane: AcOEt=1:1);

MS (El) m/z 342 (M⁺).

EXAMPLE 1(13)

1-(5-hydroxy-1-naphthyl)sulfonyl-3-phenoxy-2RS-propanol ##STR258##

By using the compound prepared in Reference Example 29(2), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.26 (hexane: AcOEt=1:1);

MS (El): m/z 358 (M⁺).

EXAMPLE 2

2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester ##STR259##

To a solution of the compound prepared in Example 1 (4.54 g) in acetone(25 ml), potassium carbonate (2.66 g) and bromoacetic acid methyl ester(1.46 ml) were added. The mixture was stirred overnight. Ethyl acetate(25 ml) was added to the reaction mixture. The mixture was filtrated.The filtrate was concentrated. The residue was purified on silica gelcolumn chromatography (hexane: AcOEt=7:3) to give the present inventioncompound (4.95 g) having the following physical data.

TLC: Rf 0.46 (AcOEt: benzene=3:17);

MS (APCl): m/z 409 (M⁺ +1--H₂ O).

EXAMPLE 2(1)

2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}acetic acid methylester ##STR260##

By using the compound prepared in Example 1(1), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.36 (hexane: AcOEt=1:1);

MS (El): m/z 442 (M⁺).

EXAMPLE 2(2)

2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}acetic acid methyl ester ##STR261##

By using the compound prepared in Example 1(2), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.40 (hexane AcOEt=1:1);

MS (El): m/z 458 (M⁺).

EXAMPLE 2(3)

2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acidmethyl ester ##STR262##

By using the compound prepared in Example 1(3), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.46 (AcOEt: benzene=3:17);

MS (APCl): m/z 409 (M⁺ +1--H₂ O).

EXAMPLE 2(4)

2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acidmethyl ester ##STR263##

By using the compound prepared in Example 1(4), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.46 (AcOEt: benzene=3:17);

MS (APCl): m/z 409 (M⁺ +1--H₂ O).

EXAMPLE 2(5)

2-[5-(2RS -hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic acidmethyl ester ##STR264##

By using the compound prepared in Example 1(5), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.30 (AcOEt: benzene=3:17);

MS (El): m/z 412 (M⁺).

EXAMPLE 2(6)

2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]aceticacid methyl ester ##STR265##

By using the compound prepared in Example 1(6), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.22 (AcOEt);

MS (El) m/z 412 (M⁺ --O).

EXAMPLE 2(7)

2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]aceticacid methyl ester ##STR266##

By using the compound prepared in Example 1(7), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.18 (AcOEt: benzene=1:4);

MS (El): m/z 444 (M⁺).

EXAMPLE 2(8)

2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic acidmethyl ester ##STR267##

By using the compound prepared in Example 1(8), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.35 (hexane: AcOEt=2:1);

MS (El): m/z 410 (M⁺).

EXAMPLE 2(9)

2-{5-[3-(2RS-hydroxy-2-phenylethylsulfinyl)propyl]-1-naphthyloxy}aceticacid methyl ester ##STR268##

By using the compound prepared in Example 1(9), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.36 (AcOEt);

MS (El): m/z 426 (M⁺).

EXAMPLE 2(10)

2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1-naphthyloxy}aceticacid methyl ester ##STR269##

By using the compound prepared in Example 1(10), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.10(hexane: AcOEt=2:1); MS (El): m/z 442 (M⁺).

EXAMPLE 2(11)

2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid methylester ##STR270##

By using the compound prepared in Example 1(11), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.42 (hexane: AcOEt=1:1);

MS (El): m/z 398 (M⁺).

EXAMPLE 2(12)

2-[5-(2RS -hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acidmethyl ester ##STR271##

By using the compound prepared in Example 1(12), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.29 (hexane: AcOEt=1:1);

MS (El): m/z 414 (M⁺).

EXAMPLE 2(13)

2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic acidmethyl ester ##STR272##

By using the compound prepared in Example 1(13), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.31 (hexane: AcOEt=1:1);

MS (El): m/z 430 (M⁺).

EXAMPLE 3

2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}aceticacid ##STR273##

To a solution of the compound prepared in Example 2 (4.80 g) indimethoxyethane-methanol (30 ml-15 ml), 2N aqueous solution of sodiumhydroxide (8 ml) was added at 0° C. The mixture was stirred for 1 hourat 0° C. 2N aqueous solution of hydrochloric acid (8.5 ml) was added tothe reaction solution in order to be neutralized. The mixture wasextracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium chloride, dried over with anhydrousmagnesium sulfate and concentrated. The residue was recrystalized fromAcOEt-hexane to give the present invention compound (4.07 g) having thefollowing physical data.

TLC: Rf 0.22 (CHCl₃ : MeOH=15:1);

MS (El): m/z 412 (M⁺);

NMR (DMSO-d6): δ 8.25 (1H, d, J=8 Hz), 7.71 (1H, d, J=8 Hz), 7.50-7.16(5H, m), 7.02-6.69 (4H, m), 4.78 (2H, s), 4.24-4.38 (7H, m), 2.90-2.53(2H, m).

EXAMPLE 3(1)

2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}aceticacid ##STR274##

By using the compound prepared in Example 2(1), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.26 (CHCl₃ : MeOH=15:1);

MS (El): m/z 428 (M⁺)

NMR (DMSO-d6): δ 8.42 (1H, d, J=8 Hz), 7.73 (1H, d, J=8 Hz), 7.60-7.21(5H, m), 6.98-6.82 (4H, m), 4.81 (2H, s), 4.76-4.38 (6H, m), 4.06-3.97(1 H, m), 2.90-2.53 (2H, m).

EXAMPLE 3(2)

2-{5-[2-(2RS-hydroxy-3-phenoxypropysulffonyl)ethyl]-1-naphthyloxy}aceticacid ##STR275##

By using the compound prepared in Example 2(2), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.18 (CHCl₃ : MeOH=15:1);

MS (El): m/z 444 (M⁺), 404, 167, 115;

NMR (DMSO-d6): δ 8.22 (1H, d, J=8 Hz), 7.59 (1H, d, J=8 Hz), 7.42-7.14(7H, m), 6.89-6.66 (2H, m), 4.78 (2H, s), 4.24-3.88 (7H, m), 2.90-2.53(2H, m).

EXAMPLE 3(3)

2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid##STR276##

By using the compound prepared in Example 2(3), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.26 (CHCl₃ : MeOH: AcOH=19:1:0.1);

MS (APCl): m/z 411 (M⁺ -1), 353;

m.p. 114.0-115.5° C.;

NMR (DMSO-d6): δ 8.20-8.10 (1H, m), 7.64 (1H, d, J=8.6 Hz), 7.50-7.35(3H, m), 7.35-7.20 (2H, m), 7.00-6.85 (4H, m), 5.25 (1H, br.), 4.87 (2H,s), 3.96 (3H, m), 3.37-3.22 (2H, m), 2.98-2.65 (4H, m).

EXAMPLE 3(4)

2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acid##STR277##

By using the compound prepared in Example 2(4), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.26 (CHCl₃ : MeOH: AcOH=19:1:0.1);

MS (APCl): m/z 411 (M⁺ -1), 353;

m.p. 114.0-115.5° C.;

NMR (DMSO-d6): δ 8.20-8.10 (1H, m), 7.64 (1H, d, J=8.6 Hz), 7.50-7.35(3H, m), 7.35-7.20 (2H, m), 7.00-6.85 (4H, m), 5.25 (1H, br.), 4.87 (2H,s), 3.96 (3H, m), 3.37-3.22 (2H, m), 2.98-2.65 (4H, m).

EXAMPLE 3(5)

2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic acid##STR278##

By using the compound prepared in Example 2(5), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.21 (MeOH: CHCl₃ =3:7);

MS (El): m/z 398 (M⁺);

m.p. 105-107° C.;

NMR (DMSO-d6+CDCl₃): δ8.32 (1H, d, J=8 Hz), 7.75 (1H, d, J=8 Hz),7.58-7.14 (5H, m), 7.00-6.70 (4H, m), 4.78 (2H, s, CH₂ COO), 4.60-3.80(7H, m), 2.87-2.60 (2H, m).

EXAMPLE 3(6)

2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]aceticacid ##STR279##

By using the compound prepared in Example 2(6), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.16 (MeOH: CHCl₃ =3:7);

MS (El): m/z 414 (M⁺), 396 (M⁺ --H₂ O);

NMR (CD₃ OD+CDCl₃): δ 8.45 (1H, d, J=8 Hz), 7.73 (1H, d, J=8Hz),7.62-7.38 (3H, m), 7.34-7.19 (2H, m), 7.00-6.82 (4H, m), 5.05-4.40 (5H,m), 4.08-3.96 (2H, m), 3.44-3.05 (2H, m).

EXAMPLE 3(7)

2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]aceticacid ##STR280##

By using the compound prepared in Example 2(7), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.17 (MeOH: CH₂ Cl₂ =1:5);

MS (El): m/z 430 (M⁺);

m.p. 186-190° C.;

NMR (CD₃ OD+CDCl₃): δ 8.48 (1H, d, J=8 Hz), 7.82 (1H, d, J=8Hz), 7.70(1H, d, J=7 Hz), 7.63-7.40 (2H, m), 7.40-7.22 (2H, m), 7.10-6.77 (4H,m), 5.02 (1H, d, J=15 Hz), 4.92 (1H, d, J=15 Hz), 4.81 (2H, s),4.75-4.54 (1H, m), 4.20-3.70 (2H, m), 3.40-3.33 (1H, m), 3.33-3.15 (1H,m).

EXAMPLE 3(8)

2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic acid##STR281##

By using the compound prepared in Example 2(8), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.13 (MeOH: CH₂ Cl₂ =1:5);

MS (El): m/z 396 (M⁺), 290, 276;

NMR (DMSO-d6): δ 14.00-12.40 (1H, br), 8.12 (1H, d, J=8 Hz), 7.65 (1H,d, J=8 Hz), 7.50-7.16 (8H, m), 6.88 (1H, d, J=7 Hz), 5.47 (1H, m), 4.87(2H, s), 4.63 (1H, m), 3.06 (2H, m), 2.75 (2H, m), 2.60-2.40 (2H,m),1.87 (2H, m).

EXAMPLE 3(9)

2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid##STR282##

By using the compound prepared in Example 2(11), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.25 (MeOH: CH₂ Cl₂ =1:5);

MS (El): m/z 384 (M⁺);

NMR (DMSO-d6): δ 8.68 (1H, d, J=4 Hz), 8.43 (1H, d, J=8 Hz), 8.40 (1H,d, J=8 Hz), 7.81 (1H, t, J=4 Hz), 7.66 (1H, d, J=4 Hz), 7.61-7.28 (3H,m), 7.01-6.90 (3H, m), 4.92-4.79 (1 H, m), 4.87 (2H, s), 4.21-3.83 (4H,m).

EXAMPLE 3(10)

2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acid##STR283##

By using the compound prepared in Example 2(12), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.29 (MeOH: CH₂ Cl₂ =1:5);

MS (El): m/z 401 (M⁺ +1);

NMR (DMSO-d6): δ 8.68 (1H, d, J=4 Hz), 8.43 (1H, d, J=8 Hz), 8.40 (1H,d, J=8 Hz), 7.81 (1H, t, J=4 Hz), 7.66 (1H, d, J=4 Hz), 7.61-7.28 (3H,m), 7.01- 6.90 (3H, m), 4.92-4.79 (1H, m), 4.87 (2H, s), 4.21-3.83 (4H,m).

EXAMPLE 3(11)

2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic acid##STR284##

By using the compound prepared in Example 2(13), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.22 (MeOH: CH₂ Cl₂ =1:5);

MS (El): m/z 416 (M⁺);

NMR (DMSO-d6): δ 8.68 (1H, d, J=4 Hz), 8.43 (1H, d, J=8 Hz), 8.40 (1H,d, J=8 Hz), 7.81 (1H, t, J=4 Hz), 7.66 (1H, d, J=4 Hz), 7.61-7.28 (3H,m), 7.01- 6.90 (3H, m), 4.92-4.79 (1H, m), 4.87 (2H, s), 4.21-3.83 (4H,m).

EXAMPLE 4

2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid methyl ester##STR285##

To a solution of the compound prepared in Example 2(10) (96 mg) inmethylene chloride (10 ml), triethylamine (0.091 ml) and mesylchloride(37.3 ml) were added at 0° C. The mixture was heated to room temperatureand stirred for 30 minutes. Water was added to the reaction mixture. Themixture was extracted with ethyl acetate. The organic layer was washedwith water and a saturated aqueous solution of sodium chloride, driedover with anhydrous sodium sulfate and concentrated. The residue waspurified on silica gel column chromatography (hexane AcOEt=2:1) to givethe present invention compound (94 mg) having the following physicaldata.

TLC: Rf 0.18 (hexane: AcOEt=2:1);

MS (El): m/z 424 (M⁺).

EXAMPLE 4(1)

2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid methyl ester##STR286##

By using the compound prepared in Example 2(9), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 4.

TLC: Rf 0.50 (benzene: AcOEt=1:2);

MS (El): m/z 408 (M⁺).

EXAMPLE 5

2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid ##STR287##

By using the compound prepared in Example 4(1), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.23 (MeOH : CH₂ Cl₂ =1:5);

MS (El): m/z 394 (M⁺),378, 320, 242, 183;

NMR (CDCl₃ -CD₃ OD): δ 8.38 (0.13H, dd, J=8, 2 Hz), 8.30 (0.87H, d, J=8Hz), 7.64-7.20 (10H, m), 6.82-6.67 (1.87H, m), 6.61 (0.13H, d, J=8 Hz),4.77 (1.74H, s), 4.75 (0.26H, s), 3.30-3.03 (4H, m), 2.40-2.15 (2H, m).

EXAMPLE 5(1)

2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid ##STR288##

By using the compound prepared in Example 4, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 5.

TLC: Rf 0.26 (MeOH: CH₂ Cl₂ =1:5);

MS (El): m/z 410 (M), 378, 352, 276, 253, 242, 215;

NMR (CDCl₃): δ 8.26 (1H, d, J=8 Hz), 7.57 (1H, d, J=9 Hz), 7.50-7.13(9H, m), 7.13-6.40 (1H, br), 6.79 (1H, d, J=15 Hz), 6.65 (1H, d, J=7Hz), 4.75 (2H, s), 3.19 (2H, t, J=8 Hz), 2.90 (2H, t, J=8 Hz), 2.22 (2H,m).

EXAMPLE 6

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-chlorophenoxy)-2RS-propanol##STR289##

By using 4-chlorophenol instead of phenol in Reference Example 2, thepresent invention compound having the following physical data wasobtained by the same procedure as Reference Example 2→Reference Example3→Reference Example 4→Reference Example 5→Reference Example 24→Example1.

TLC: Rf 0.34 (hexane: AcOEt=2:1);

MS (APCl): m/z 389, 387 (1:3, M--H⁺);

NMR (CDCl₃) δ 8.12 (1H, d, J=7.4 Hz), 7.58 (1H, d, J=8.4 Hz), 7.38 (3H,m), 7.22 (2H, d, J=6.8 Hz), 6.82 (2H, d, J=6.8 Hz), 6.82 (1H, m), 5.32(1H, s), 4.07 (1H, m), 3.96 (2H, m), 3.35 (2H, m), 2.96 (2H, m), 2.86(1H, dd, J=14, 5 Hz), 2.74 (1H, dd, J=1 4, 6.8 Hz), 2.66 (1H, d, J=3.4Hz).

EXAMPLE 6(1)

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methylphenoxy)-2RS-propanol##STR290##

By using 4-methylphenol instead of phenol in Reference Example 2, thepresent invention compound having the following physical data wasobtained by the same procedure as Example 6.

TLC: Rf 0.35 (hexane: AcOEt=2:1);

NMR (CDCl₃): δ 8.11 (1H, d, J=8.4 Hz), 7.58 (1H, d, J=8.6 Hz), 7.37 (3H,m), 7.07 (2H, d, J=8 Hz), 6.82 (1H, d, J=7.4 Hz), 6.80 (2H, d, J=8 Hz),5.39 (1H, s), 4.08 (1H, m), 4.00 (2H, m), 3.35 (2H, m), 2.95 (2H, m),2.91 (1H, dd, J=13.6, 5.2 Hz), 2.46 (1H, dd, J=13.6, 6.8 Hz), 2.70 (1H,d, J=4 Hz), 2.29 (3H, s).

EXAMPLE 6(2)

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-(4-methoxyphenoxy)-2RS-propanol##STR291##

By using 4-metyhoxyphenol instead of phenol in Reference Example 2, thepresent invention compound having the following physical data wasobtained by the same procedure as Example 6.

TLC: Rf 0.55 (hexane: AcOEt=2:1).

EXAMPLE 6(3)

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-diphenylmethoxy-2RS-propanol##STR292##

By using diphenylmethanol instead of phenol in Reference Example 2, thepresent invention compound having the following physical data wasobtained by the same procedure as Example 6.

TLC: Rf 0.29 (hexane: AcOEt=2:1)

NMR (CDCl₃): δ 8.11 (1H, m), 7.57 (1H, d, J=8.6 Hz), 7.34 (13H, m), 6.81(1H, d, J=7.4 Hz), 5.43 (1H, s), 5.38 (1H, s), 3.96 (1H, m), 3.52 (2H,d, J=5.6 Hz), 3.31 (2H, m), 2.91 (2H, m), 2.80 (1H, dd, J=5.3, 13.6 Hz),2.69 (1H, dd, J=7.2, 13.6 Hz), 2.67 (1H, d, J=4.3 Hz).

EXAMPLE 6(4)

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-[1-phenyl-1-(4-chlorophenyl)methoxy]-2RS-propanol##STR293##

By using 1-phenyl-1-(4-chlorophenyl)methanol instead of phenol inReference Example 2, the present invention compound having the followingphysical data was obtained by the same procedure as Example 6.

TLC: Rf 0.35 (hexane: AcOEt=2:1);

NMR (CDCl₃): δ 8.12 (1H, d, J=9.1 Hz), 7.57 (1H, d, J=8.4 Hz), 7.33(12H, m), 6.82 (1H, d, J=7.5 Hz), 5.40 (1H, m), 5.35 (1H, s), 3.94 (1H,m), 3.50 (2H, d, J=4.8 Hz), 3.32 (2H, m), 2.91 (2H, m), 2.73 (3H, m).

EXAMPLE 6(5)

1-[2-(5-hydroxy-1-naphthyl)ethylthio]-3-phenylthio-2RS-propanol##STR294##

By using thiophenol instead of phenol in Reference Example 2, thepresent invention compound having the following physical data wasobtained by the same procedure as Example 6.

TLC: Rf 0.41 (hexane: AcOEt=2:1).

EXAMPLE 6(6)

1-(5-hydroxy-1-naphthyl)methylthio-3-diphenylmethoxy-2RS-propanol##STR295##

By using diphenylmethanol instead of phenol in Reference Example 2, thepresent invention compound having the following physical data wasobtained by the same procedure as Reference Example 2→Reference Example3→Reference Example 4→Reference Example 5→Reference Example24(3)→Example 1.

TLC: Rf 0.17 (acetone: benzene=1:19); NMR (CDCl₃): δ 8.15 (1H, dd,J=3.0, 6.6 Hz), 7.69 (1H, d, J=8.6 Hz), 7.32 (13H, m), 6.82 (1H, d,J=7.3 Hz), 5.50 (1H, s), 5.35 (1H, s), 4.17 (2H, s), 3.94 (1H, m), 3.48(1H, d, J=5.2 Hz), 2.55-2.77 (3H, m).

EXAMPLE 6(7)

1-(5-hydroxy-1-naphthyl)methylthio-3-[1-phenyl-1-(4-chlorophenyl)methoxy]-2RS-propanol##STR296##

By using 1-phenyl-1-(4-chlorophenyl)methanol instead of phenol inReference Example 2, the present invention compound having the followingphysical data was obtained by the same procedure as Example 6(6).

TLC: Rf 0.28 (hexane: AcOEt=2:1);

NMR (CDCl₃): δ 8.16 (1H, dd, J=3.3, 6.3 Hz), 7.69 (1H, d, J=9.5 Hz),7.29 (12H, m), 6.83 (1H, d, J=7.4 Hz), 5.41 (1H, s), 5.30 (1H, s), 4.17(2H, s), 3.91 (1H, m), 3.45 (2H, d, J=5.2 Hz), 2.71 (1H, dd, J=5.2, 13.8Hz), 2.63 (1H, dd, J=2.3, 7.2 Hz), 2.57 (1H, d, J=4.1 Hz).

REFERENCE EXAMPLE 30 ##STR297##

To the suspension of sodium hydride (42 mg) in DMF (1 ml), the solutionof the compound prepared in Reference Example 15 (232 mg) in DMF (2 ml)was added at room temperature. To the mixture, THF (1 ml) andhexamethylphosphoramide (0.2 ml) were added at room temperature. Themixture was stirred for 30 minutes at room temperature and for 30minutes at 40° C. To the mixture, the solution of the compound preparedin Reference Example 5 (406 mg) in DMF (2 ml) was added at roomtemperature. The mixture was stirred for 6 hours at 50° C. The reactionmixture was added to the aqueous solution of ammonium chloride,extracted with diethylether. The organic layer was washed with water anda saturated aqueous solution of sodium chloride, dried over withanhydrous sodium sulfate and concentrated. The residue was purified onsilica gel column chromatography (hexane:AcOEt=87:13) to give the titlecompound (54.8 mg) having the following physical data.

TLC: Rf 0.37 (hexane: AcOEt=3:1);

NMR (CDCl₃): δ 8.18 (1H, m), 7.68 (1H, d, J=8 Hz), 7.45-7.20 (5H, m),7.09 (1H, d, J=8 Hz), 7.01-6.83 (3H, m), 5.39 (2H, s), 4.88-4.72 (1H,m), 4.25-3.26 (14H, m), 1.90-1.40 (6H, m) .

REFERENCE EXAMPLE 31 ##STR298##

To the solution of the compound prepared in Reference Example 15 (5.0 g)in pyridine (15 ml), tosylchloride (6.28 g) was added at -20° C. Themixture was stirred for 2 hours at room temperature. The water (2 ml)was added dropwise to the mixture to decompose superfluoustosylchloride. To the mixture, 2N aqueous solution of hydrochloric acid(80 ml) was added. The mixture was extracted with ethyl acetate. Theorganic layer was washed with water and a saturated aqueous solution ofsodium chloride, dried over with anhydrous sodium sulfate andconcentrated to obtain crude tosyl compound. The tosyl compound wasdissolved in acetone (25 ml). To the solution, sodium azide (2.8 g) andtetrabutylammonium bromide (400 mg) were added. The solution wasrefluxed over night. To the solution, sodium azide (2.8 g) was added.The solution was refluxed for 4 hours and cooled The solvent wasdistilled off. The residue was diluted with ethyl acetate, washed withwater and a saturated aqueous solution of sodium chloride, dried overwith anhydrous sodium sulfate and concentrated to give the titlecompound (5.38 g) having the following physical data. TLC: Rf 0.52(hexane: AcOEt=7:3).

REFERENCE EXAMPLE 32 ##STR299##

To the solution of the compound prepared in Reference Example 31 (1.56g) in ethyl acetate (20 ml), 5% Pd-C (50 mg) was added. The mixture wasstirred under an atmosphere of H₂ gas for 5 hours at room temperature.The solution was filtrated by Celite (Registered trade mark). Thefiltrate was concentrated and purified on silica gel columnchromatography (MeOH CHCl₃ =3:97→MeOH: CHCl₃ : propylamine=10:90:1) togive the title compound (1.02 g) having the following physical data.

TLC: Rf 0.17 (MeOH: CHCl₃ =1:3);

NMR (CDCl₃): δ 8.20 (1H, m), 7.69 (1H, d, J=8 Hz), 7.48-7.27 (3H, m),7.11 (1H, d, J=8 Hz), 5.40 (2H, s), 3.53 (3H, s), 3.27-3.04 (4H, m),1.35 (2H, brs, NH₂) .

REFERENCE EXAMPLE 33 ##STR300##

The solution of the compound prepared in Reference Example 32 (300 mg)and (±)-1,2-epoxy-3-phenoxypropane (195 mg) in iso-propanol (3 ml) wasstirred for 2 days at room temperature. The reaction mixture wasconcentrated. The residue was purified on silica gel columnchromatography (MeOH: CHCl₃ =3:97→1:9) to give the title compound (270mg) having the following physical data.

TLC: Rf 0.26 (MeOH: CHCl₃ =1:9);

NMR (CDCl₃): δ 8.22 (1H, m), 7.71 (1H, d, J=8 Hz), 7.47-7.21 (5H, m),7.11 (1H, d, J=8 Hz), 6.99-6.84 (3H, m), 5.40 (2H, s), 4.15-3.92 (3H,m), 3.55 (3H, s), 3.20 (2H, t, J=8 Hz), 3.13-2.76 (4H, m), 2.53 (2H,brs, OH & NH).

EXAMPLE 7

1-[2-(5-hydroxy-1-naphthyl)ethoxy]-3-phenoxy-2RS-propanol ##STR301##

By using the compound prepared in Reference Example 30, the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.18 (hexane: AcOEt=2:1);

NMR (CDCl₃): δ 8.11 (1H, m), 7.63 (1H, d, J=8 Hz), 7.46-7.21 (5H, m),7.02-6.77 (4H, m), 5.49 (1H, s), 4.14 (1H, m), 3.96 (2H, d, J=5 Hz),3.85 (2H, t, J=7 Hz), 3.63 (2H, m), 3.35 (2H, t, J=7 Hz), 2.48 (1H, d,J=4 Hz) .

EXAMPLE 7(1)

1-[2-(5-hydroxy-1-naphthyl)ethylamino]-3-phenoxy-2RS-propanol ##STR302##

By using the compound prepared in Reference Example 33, the presentinvention compound having the following physical data was obtained bythe same procedure as Example 1.

TLC: Rf 0.10 (MeOH: CHCl₃ =1:9);

NMR (CDCl₃ +DMSO=1:4): δ 8.15 (1H, m), 7.54 (1H,d, J=8 Hz), 7.40-7.20(5H, m), 7.00-6.84 (4H, m), 4.16-3.90 (3H, m), 3.80-2.50 (3H, br), 3.29(2H, t, J=7 Hz), 3.14-2.75 (4H, m).

REFERENCE EXAMPLE 34 ##STR303##

The mixture of the compound prepared in Example 7(1) (150 mg),trifluoroacetic acid ethyl ester (1 ml), triethylamine (0.5 ml) andethanol (3 ml) was stirred for 5 hours at room temperature. The reactionmixture was concentrated and purified on silica gel columnchromatography (hexane AcOEt=5:2) to give the title compound (1 55 mg)having the following physical data.

TLC: Rf 0.53 (hexane: AcOEt=1:1);

NMR (CDCl₃): rotational isomer, δ 8.21-8.10 (1 H, m), 7.38 and 7.53(combined 1H, each d, J=8 Hz), 7.48-7.20 (5H, m), 7.04-6.89 (4H, m),5.53 (1H, brs), 4.40-3.27 (9H, m), 3.10 and 2.40 (combined 1H, each m) .

EXAMPLE 8

2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}-aceticacid methyl ester ##STR304##

By using the compound prepared in Example 6, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.27 (acetone: benzene=1:19);

NMR (CDCl₃): δ 8.30 (1H, d, J=7.4 Hz), 7.62 (1H, d, J=8.6 Hz), 7.41 (3H,m), 7.22 (2H, d, J=9 Hz), 6.82 (2H, d, J=9 Hz), 6.72 (1H, d, J=7.4 Hz),4.83 (2H, s), 4.06 (1H, m), 3.96 (2H, m), 3.04 (3H, s), 3.35 (2H, m),2.95 (2H, m), 2.84 (1H, dd, J=14, 5 Hz), 2.73 (1H, dd, J=14, 7 Hz), 2.65(1 H, d, J=4 Hz).

EXAMPLE 8(1)

2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}-aceticacid methyl ester ##STR305##

By using the compound prepared in Example 6(1), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.37 (acetone: benzene=1:19);

NMR (CDCl₃): δ 8.29 (1H, d, J=8 Hz), 7.64 (1H, d, J=8.8 Hz), 7.39 (3H,m), 7.07 (2H, d, J=8.8 Hz), 6.80 (2H, d, J=8.8 Hz), 6.72 (1H, d, J=8.8Hz), 4.82 (2H, s), 4.08 (1H, m), 3.98 (2H, m), 3.83 (3H, s), 3.45 (2H,t, J=8.6 Hz), 2.94 (2H, t, J=8.6 Hz), 2.88 (2H, dd, J=14, 5.2 Hz), 7.75(2H, dd, J=1 4, 6.8 Hz), 2.68 (1H, d, J=4 Hz), 2.29 (3H, s).

EXAMPLE 8(2)

2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}-aceticacid methyl ester ##STR306##

By using the compound prepared in Example 6(2), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.41 (acetone: benzene=1:9);

NMR (CDCl₃): δ 8.30 (1H, d, J=7.8 Hz), 7.63 (1H, d, J=8.6 Hz), 7.41 (3H,m), 6.83 (4H, s), 6.72 (1H, d, J=8.6 Hz), 4.82 (2H, s), 4.05 (1H, m),3.96 (2H, m), 3.83 (3H, s), 3.77 (3H, s), 3.34 (2H, t, J=6.6 Hz), 2.93(2H, t, J=6.6 Hz), 2.88 (1H, dd, J=14, 5 Hz), 2.75 (1H, dd, J=14, 7.2Hz), 2.69 (1H, d, J=4 Hz).

EXAMPLE 8(3)

2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid methyl ester ##STR307##

By using the compound prepared in Example 6(3), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.33 (acetone: benzene=1:19);

NMR (CDCl₃): δ 8.29 (1H, m), 7.62 (1H, d, J=8.6 Hz), 7.33 (13H, m), 6.72(1H, d, J=7.7 Hz), 5.39 (1H, s), 4.82 (2H, s), 3.95 (1H, m), 3.83 (3H,s), 3.53 (2H, d, J=5.7 Hz), 2.90 (2H, m), 2.79 (1H, dd, J=5.3, 13.6 Hz),2.69 (1H, dd, J=7.2, 13.6 Hz), 2.63 (1H, d, J=2.8 Hz).

EXAMPLE 8(4)

2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-ethyl]-1-naphthyloxy}aceticacid methyl ester ##STR308##

By using the compound prepared in Example 6(4), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.26 (acetone: benzene=1:19);

NMR (CDCl₃): δ 8.29 (1H, d, J=8.1 Hz), 7.62 (1H, d, J=8.5 Hz), 7.33(12H, m), 6.72 (1H, d, J=7.6 Hz), 5.35 (1H, s), 4.82 (2H, s), 3.93 (1H,m), 3.83 (3H, s), 3.50 (1H, d, J=4.8 Hz), 3.32 (2H, m), 2.90 (2H, m),2.76 (2H, m), 2.60 (1H, d, J=4.3 Hz).

EXAMPLE 8(5)

2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-naphthyloxy}aceticacid methyl ester ##STR309##

By using the compound prepared in Example 6(5), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.33 (acetone: benzene=1:19).

EXAMPLE 8(6)

2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]aceticacid methyl ester ##STR310##

By using the compound prepared in Example 6(6), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.33 (acetone: benzene=1:19);

NMR (CDCl₃): δ 8.33 (1H, m), 7.75 (1H, d, J=8.6 Hz), 7.33 (13H, m), 6.74(1H, d, J=7.7 Hz), 5.35 (1H, s), 4.82 (2H, s), 4.18 (2H, s), 3.94 (1H,m), 3.83 (3H, s), 3.48 (2H, d, J=5.2 Hz), 2.71 (1H, dd, J=5.3, 13.9 Hz),2.59 (1H, dd, J=7.2, 13.9 Hz), 2.58 (1H, d, J=4.1 Hz).

EXAMPLE 8(7)

2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]methyl-1-naphthyloxy}aceticacid methyl ester ##STR311##

By using the compound prepared in Example 6(7), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.29 (acetone: benzene=1:19);

NMR (CDCl₃): δ 8.33 (1H, m), 7.74 (1H, d, J=8.8 Hz), 7.33 (12H, m), 6.74(1H, d, J=7.7 Hz), 5.30 (1H, s), 4.82 (2H, s), 4.17 (2H, s), 3.91 (1H,m), 3.83 (3H, s), 3.44 (2H, d, J=5.2 Hz), 2.70 (1H, dd, J=5.3, 13.9 Hz),2.62 (1H, dd, J=2.0, 7.2 Hz), 2.54 (1H, d, J=3.8 Hz).

EXAMPLE 8(8)

2-{5-[2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic acidmethyl ester ##STR312##

By using the compound prepared in Example 7, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.37 (AcOEt: CH₂ Cl₂ =1:9);

NMR (CDCl₃): δ 8.29 (1H, m), 7.69 (1H, d, J=8 Hz), 7.47-7.20 (5H, m),7.01-6.82 (3H, m), 6.71 (1H, d, J=8 Hz), 4.82 (2H, s), 4.12 (1H, m),3.95 (2H, d, J=5.5 Hz), 3.96-3.77 (5H, m), 3.62 (2H, m), 3.35 (2H, t,J=7 Hz), 2.44 (1H, d, J=3 Hz).

EXAMPLE 9

2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}-aceticacid ##STR313##

By using the compound prepared in Example 8, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.61 (MeOH: CHCl₃ : AcOH=1:18:1);

MS (APCl): m/z 445, 447 (3:1), (M--H)+;

NMR (DMSO-d6): δ 13.08 (1H, brs), 8.15 (1H, t, J=4.4 Hz), 7.63 (1H, d,J=8.8 Hz), 7.43 (3H, m), 7.31 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz),6.89 (1H, d, J=8.8 Hz), 5.29 (1H, m), 4.87 (2H, s), 3.95 (3H, m), 3.30(2H, m), 2.90 (2H, t, J=7 Hz), 2.80 (1H, dd, J=14, 4 Hz), 2.70 (1H, dd,J=14, 6 Hz).

EXAMPLE 9(1)

2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}-aceticacid ##STR314##

By using the compound prepared in Example 8(1), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.60 (MeOH: CHCl₃ : AcOH=1:18:1);

MS (APCl): m/z 425 (M--H)+;

NMR (DMSO-d6): δ 13.07 (1H, brs), 8.14 (1H, t, J=4.2 Hz), 7.63 (1H, d,J=8.6 Hz), 7.43 (3H, m), 7.07 (2H, d, J=8.2 Hz), 6.89 (1H, d, J=8.6 Hz),6.72 (2H, d, J=8.2 Hz), 5.23 (1H, d, J=5 Hz), 4.87 (2H, s), 3.95 (3H,m), 3.30 (2H, m), 2.90 (2H, t, J=8 Hz), 2.82 (1H, dd, J=14, 6 Hz), 2.70(1H, dd, J=14, 6 Hz), 2.22 (3H, s).

EXAMPLE 9(2)

2-{5-[2-(2RS-hydroxy-3-(4-methyoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}-aceticacid ##STR315##

By using the compound prepared in Example 8(2), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf0.56 (MeOH: CHCl₃ : AcOH=1:18:1);

MS (APCl): m/z 441 (M--H)+;

NMR (DMSO-d6): δ 13.07 (1H, brs), 8.14 (1H, t, J=6 Hz), 7.63 (1H, d,J=8.4 Hz), 7.43 (3H, m), 6.89 (1H, d, J=6 Hz), 6.85 (4H, s), 5.22 (1H,d, J=4.4 Hz),4.88 (2H, s), 3.90 (3H, m), 3.69 (3H, s), 3.25 (2H, m),2.88 (2H, t, J=9 Hz), 2.82 (1H, dd, J=13, 4 Hz), 2.68 (1 H, dd, J=13, 6Hz).

EXAMPLE 9(3)

2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid ##STR316##

By using the compound prepared in Example 8(3), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.60 (MeOH: CHCl₃ : AcOH=10:100:1);

MS (FAB): m/z 503 (M+1)+, 229, 207;

NMR (CDCl₃): δ 8.25 (1H, d, J=8.0 Hz), 7.63 (1H, d, J=8.4 Hz), 7.33(13H, m), 6.74 (1H, d, J=7.7 Hz), 5.38 (1H, s), 4.84 (2H, s), 3.94 (1H,m), 3.51 (2H, d, J=4.8 Hz), 3.31 (2H, m), 2.89 (2H, m), 2.78 (1H, dd,J=5.6, 13.8 Hz), 2.66 (1H, dd, J=7.2, 13.8 Hz).

EXAMPLE 9(4)

2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}aceticacid ##STR317##

By using the compound prepared in Example 8(5), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.56 (MeOH: CHCl₃ : AcOH=1:18:1);

MS (APCl): m/z 427 (M--H)+;

NMR (DMSO-d6): δ 13.09 (1H, brs), 8.14 (1H, dd, J=7, 3.2 Hz), 7.62 (1H,d, J=8.6 Hz), 7.50-7.22 (7H, m), 7.22-7.10 (1H, m), 6.89 (1H, d, J=7.2Hz), 5.31 (1H, d, J=4.8 Hz), 4.87 (2H, s), 3.78 (1H, m), 3.25 (2H, t,J=8 Hz), 3.16 (1H, dd, J=13, 5 Hz), 3.03 (1H, dd, J=13, 6 Hz), 2.85 (2H,t, J=8 Hz), 2.80 (1H, dd, J=1 3, 5 Hz), 2.69 (1H, dd, J=13, 6 Hz).

EXAMPLE 9(5)

2-[5-(2RS-hydroxy-3-dipheny[methoxypropylthio)methyl-1-naphthyloxy]aceticacid ##STR318##

By using the compound prepared in Example 8(6), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.55 (MeOH: CHCl₃ : AcOH=10:100:1);

MS (FAB): m/z 489 (M+1)+, 338;

NMR (CDCl₃): δ 8.30 (1H, m), 7.77 (1H, d, J=8.5 Hz), 7.35 (13H, m), 6.76(1H, d, J=7.9 Hz), 5.34 (1H, s), 4.85 (2H, s), 4.16 (2H, s), 3.94 (1H,m), 3.47 (2H, d, J=5.1 Hz), 2.71 (1H, dd, J=5.2, 13.8 Hz), 2.59 (1H, dd,J=7.2, 13.8 Hz).

EXAMPLE 9(6)

2-{5-(2-(2RS-hydroxy-3-phenoxypropoxy)ethyl]-1-naphthyloxy}acetic acid##STR319##

By using the compound prepared in Example 8(8), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.17 (MeOH: CHCl₃ =1:3);

NMR (DMSO-d6): δ 13.00 (1H, brs), 8.13 (1H, dd, J=8, 2 Hz), 7.66 (1H, d,J=9 Hz), 7.50-7.20 (5H, m), 6.98-6.82 (4H, m), 5.07 (1H, m), 4.87 (2H,s), 4.00-3.10 (9H, m).

EXAMPLE 10

1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-naphthalene##STR320##

By using bromoacetonitrile instead of bromoacetic acid methyl ester inExample 2 and the compound prepared in Example 1, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.33 (benzene: AcOEt=17:3);

NMR (CDCl₃) δ 8.17 (1H, m), 7.73 (1H, d, J=8 Hz), 7.52-7.23 (5H, m),7.05-6.85 (4H, m), 4.95 (2H, s, --OCH₂), 4.20-3.96 (3H, m), 3.38 (2H, t,J=7 Hz), 3.03-2.60 (5H, m).

EXAMPLE 10(1)

1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-chlorophenoxy)propylthio]ethyl}-naphthalene##STR321##

By using the compound prepared in Example 6, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 10.

TLC: Rf 0.45 (acetone: benzene=1:9);

MS (El): m/z 427, 429 (3:1) (M)+, 387, 389 (3:1) (M-40)+;

NMR (CDCl₃): δ 8.14 (1H, d, J=7.6 Hz), 7.72 (1H, d, J=8.6 Hz), 7.43 (3H,m), 7.24 (2H, d, J=9.2 Hz), 6.93 (1H, d, J=7.6 Hz), 6.82 (2H, d, J=9.2Hz), 4.97 (2H, s), 4.06 (1H, m), 3.97 (2H, m), 3.36 (2H, t, J=7 Hz),2.95 (2H, t, J=7 Hz), 2.89 (1H, dd, J=13, 5.2 Hz), 2.75 (1H, dd, J=13, 7Hz), 2.66 (1H, d, J=4.2 Hz).

EXAMPLE 10(2)

1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methylphenoxy)propylthio]ethyl}-naphthalene##STR322##

By using the compound prepared in Example 6(1), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 10.

TLC: Rf 0.45 (acetone: benzene=1:9);

MS (El): m/z 407 (M)+, 367 (M-40)+;

NMR (DMSO-d6): δ 8.14 (1H, t, J=7.6 Hz), 7.73 (1H, d, J=8.8 Hz), 7.43(3H, m), 7.08 (2H, d, J=8.8 Hz), 6.94 (1H, d, J=7.6 Hz), 6.80 (2H, d,J=8.2 Hz), 4.96 (2H, s), 4.08 (1H, m), 3.97 (2H, m), 3.37 (2H, t, J=7Hz), 2.95 (2H, t, J=7 Hz), 2.90 (1H, dd, J=14, 5.2 Hz), 2.75 (1H, dd,J=14, 6.8 Hz), 2.68 (1H, d, J=4.2 Hz), 2.29 (3H, s).

EXAMPLE 10(3)

1-cyanomethoxy-5-{2-[2RS-hydroxy-3-(4-methoxyphenoxy)propylthio]ethyl}-naphthalene##STR323##

By using the compound prepared in Example 6(2), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 10.

TLC: Rf 0.38 (acetone: benzene=1:9);

MS (El): m/z 423 (M)+;

NMR (DMSO-d6): δ 8.16 (1H, t, J=7.5 Hz), 7.73 (1H, d, J=8.6 Hz), 7.46(3H, m), 6.94 (1H, d, J=7 Hz), 6.83 (4H, s), 4.97 (2H, s), 4.06 (1H, m),3.97 (2H, m), 3.77 (3H, s), 3.37 (2H, t, J=7.4 Hz), 2.95 (2H, t, J=7.4Hz), 2.89 (1H, dd, J14, 6.4 Hz), 2.76 (1H, dd, J=13, 6.8 Hz), 2.68 (1H,d, J=4 Hz).

EXAMPLE 10(4)

1-cyanomethoxy-5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-naphthalene##STR324##

By using the compound prepared in Example 6(3), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 10.

TLC: Rf 0.32 (acetone: benzene=1:19);

MS (FAB): m/z 484 (M+1)+, 443, 391, 168;

NMR (CDCl₃): δ 8.13 (1H, d, J=9.2 Hz), 7.72 (1H, d, J=8.7 Hz), 7.34(13H, m), 6.93 (1H, d, J=7.7 Hz), 5.39 (1H, s), 4.95 (1H, s), 3.95 (1H,m), 3.52 (1H, d, J=5.7 Hz), 3.33 (2H, dd, J=7.3, 9.7 Hz), 2.90 (2H, m),2.83 (1H, dd, J=5.3, 13.7 Hz), 2.68 (1H, dd, J=7.2, 13.7 Hz), 2.63 (1H,d, J=4.2 Hz).

EXAMPLE 10(5)

1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]naphthalene##STR325##

By using the compound prepared in Example 6(5), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 10.

TLC: Rf 0.33 (acetone: benzene=1:19);

MS (El): m/z 409 (M)+;

NMR (CDCl₃): δ 8.13 (1H, d, J=7.8 Hz), 7.70 (1H, d, J=8.8 Hz), 7.47 (1H,d, J=7.2 Hz), 7.42-7.34 (4H, m), 7.34-7.10 (3H, m), 4.97 (2H, s), 3.82(1H, m), 3.33 (2H, t, J=7 Hz), 3.15 (1H, dd, J=13.8, 5.2 Hz), 3.03 (1H,dd, J=13.8, 6.6 Hz), 2.89 (2H, t, J=7 Hz), 2.84 (1H, dd, J=13.8, 4.6Hz), 2.68 (1H, dd, J=13.8, 7.4 Hz).

EXAMPLE 10(6)

1-cyanomethoxy-5-[(2RS-hydroxy-3-diphenylmethoxy)propylthiomethyl]-naphthalene##STR326##

By using the compound prepared in Example 6(6), the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 10.

TLC: Rf 0.30 (acetone: benzene=1:19);

MS (FAB): m/z 302 (M--C13H11)+, 196, 168;

NMR (CDCl₃): δ 8.17 (1H, dd, J=2.9, 6.6 Hz), 7.85 (1H, d, J=8.7 Hz),7.36 (13H, m), 6.95 (1H, d, J=7.7 Hz), 5.35 (1H, s), 4.96 (2H, s), 4.18(2H, s), 3.94 (1H, m), 3.49 (2H, d, J=5.3 Hz), 2.71 (1H, dd, J=5.2, 13.7Hz), 2.59 (1H, dd, J=7.2, 13.7 Hz), 2.56 (1H, d, J=7.3 Hz).

EXAMPLE 11

2-{5-[2-(2RS-hydroxy-3-phenoxypropylamino)ethyl]-1-naphthyloxy}aceticacid ##STR327##

By using the compound prepared in Reference Example 34, the presentinvention compound having the following physical data was obtained bythe same procedure as Example 2→Example 3.

TLC: Rf 0.37 (MeOH: CHCl₃ : AcOH=2:6:1);

MS (FAB): m/z 396 ((M+H)+);

NMR (DMSO-d6): δ 8.18 (1H, d, J=8 Hz), 7.40-7.20 (4H, m), 7.14-7.07 (4H,m), 6.72-6.60 (2H, m), 4.58 (2H, s), 4.37-2.90 (12H, m).

EXAMPLE 12

2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-ethyl]-1-naphthyloxy}ethanol##STR328##

By using 2-bromo ethanol instead of bromoacetic acid methyl ester inExample 2 and the compound prepared in Example 6(4), the presentinvention compound having the following physical data was obtained bythe same procedure as Example 2.

TLC: Rf 0.19 (hexane: AcOEt=2:1);

MS (APCl): m/z 523 (M+1)+, 305, 215, 201;

NMR (DMSO-d6): δ 8.20 (1H, dd, J=2.1, 7.6 Hz), 7.59 (1H, d, J=8.7 Hz),7.32 (12H, m), 6.84 (1H, d, J=7.8 Hz), 5.34 (1H, s), 4.27 (2H, m), 4.11(2H, m), 3.92 (1H, m), 3.49 (2H, d, J=5.4 Hz), 3.32 (2H, dd, J=7.1, 9.6Hz), 2.90 (2H, m), 2.78 (1H, dd, J=5.3, 11.7 Hz), 2.70 (1H, dd, J=2.3,7.1 Hz), 2.61 (1H, d, J=2.5 Hz), 2.08 (1H, m).

REFERENCE EXAMPLE 35 ##STR329##

To the solution of benzyloxycarbonylaniline (2.32 g) in anhydrous DMF(30 ml), sodium hydride (426 mg) was added under an atmosphere of argongas at 0° C. The mixture was stirred for 30 minutes at room temperature.To the mixture, the compound prepared in Reference Example 1 (2.65 g)was added. The mixture was stirred for 1 hour at 80° C. To the reactionmixture, water was added to decompose the superfluous sodium hydride.The mixture was extracted with ethyl acetate, washed with water and asaturated aqueous solution of sodium chloride, dried over with anhydrousmagnesium sulfate and concentrated under the reduced pressure. Theresidue was purified on silica gel column chromatography (hexane:AcOEt=6:1) to give the title compound (2.52 g) having the followingphysical data.

TLC: Rf 0.36 (hexane: AcOEt=4:1).

REFERENCE EXAMPLE 36 ##STR330##

The solution of the compound prepared in Reference Example 35 (2.52 g)in aqueous 80% acetic acid solution (25 ml) was stirred for 10 hours atroom temperature. The reaction mixture was concentrated under thereduced pressure. The residue was purified on silica gel columnchromatography (CHCl₃ : MeOH=30:1) to give the title compound (1.69 g)having the following physical data.

TLC: Rf 0.09 (hexane: AcOEt=1:1).

REFERENCE EXAMPLE 37 ##STR331##

To the solution of the compound prepared in Reference Example 36 (328mg) in pyridine (2.5 ml), tosylchloride (217 mg) was added under anatmosphere of argon gas at -20° C. The mixture was stirred for 3.5 hoursat room temperature. To the reaction mixture, a small amount of waterwas added. The mixture was stirred for 10 minutes, extracted with ethylacetate, washed with 1N aqueous solution of hydrochloric acid, water anda saturated aqueous solution of sodium chloride succeedingly, dried overwith anhydrous magnesium sulfate and concentrated under the reducedpressure to give the title compound (522 mg) having the followingphysical data. This residue was used in the next reaction withoutpurification.

TLC: Rf 0.55 (hexane: AcOEt=1:1).

REFERENCE EXAMPLE 38 ##STR332##

To the ethanol (3.0 ml), sodium hydride (56 mg) was added under anatmosphere of argon gas at 0° C. The mixture was stirred for 10 minutes.To the mixture, the compound prepared in Reference Example 21 (310 mg)and the compound prepared in Reference Example 37 (522 mg) in ethanol(3.0 ml) was added dropwise. The mixture was stirred for 2 hours at roomtemperature. To the reaction mixture, a saturated aqueous solution ofammonium chloride was added to decompose the superfluous reagent. Thereaction mixture was extracted with ethyl acetate, washed with water anda saturated aqueous solution of sodium chloride, dried over withanhydrous magnesium sulfate and concentrated under the reduced pressure.The residue was purified on silica gel column chromatography (hexane:AcOEt=3:1) to give the title compound (427 mg) having the followingphysical data.

TLC: Rf 0.36 (hexane: AcOEt=2:1).

REFERENCE EXAMPLE 39 ##STR333##

By using the compound prepared in Reference Example 38, the titlecompound having the following physical data was obtained by the sameprocedure as Example 1→Example 12.

TLC: Rf 0.20 (hexane: AcOEt=1:1);

NMR (CDCl₃): δ 8.21 (1H, m), 7.60 (1H, d, J=8.6 Hz), 7.33-7.55 (7H, m),7.18 (1H, m), 6.85 (1H, d, J=7.6 Hz), 6.69 (1H, m), 4.27 (2H, m),3.99-4.14 (3H, m), 3.80 (1H, dd, J=6.6, 9.2 Hz), 3.35 (2H, m), 2.91-3.06(3H, m), 2.78 (1H, dd, J=7.4, 13.8 Hz), 2.11 (1H, t, J=6.4 Hz).

EXAMPLE 13

2-{5-[2-(2RS-hydroxy-3-phenylaminopropylthio)ethyl]-1-naphthyloxy}ethanol##STR334##

To the solution of the compound prepared in Reference Example 39 (138mg) in methanol (10 ml), aqueous 40% sodium hydroxide solution (0.5 ml)was added at room temperature. The solution was stirred for 7 days. Themixture was concentrated to the volume of about 3.0 ml, extracted withethyl acetate, washed with water and a saturated aqueous solution ofsodium chloride, dried over with anhydrous magnesium sulfate andconcentrated under the reduced pressure. The residue was purified onsilica gel column chromatography (CHCl₃ : MeOH=50:1) to give the presentinvention compound (116 mg) having the following physical data.

TLC: Rf 0.62 (MeOH: CHCl₃ =1:10);

MS (APCl): m/z 398 (M+1)+, 380, 245, 215;

NMR (CDCl₃): δ 8.21 (1H, dd, J=2.2, 7.6 Hz), 7.59 (1H, d, J=8.6 Hz),7.34-7.48 (3H, m), 7.12-7.24 (2H, m), 6.85 (1H, J=7.6 Hz), 6.73 (1H, t,J=7.2 Hz), 6.63 (2H, d, J=7.6 Hz), 4.27 (2H, t, J=4.2H), 3.82-4.18 (4H,m), 3.25-3.38 (3H, m), 3.06 (1 H, dd, J=7.4,13.0Hz), 2.95 (1 H, d,J=8.4Hz), 2.92 (1 H, d, J=9.2Hz), 2.77 (1H, dd, J=4.4, 13.8 Hz),2.57-2.68 (2H, m), 2.10 (1H, m).

EXAMPLE 14

1-(tetrazol-5-yl-methoxy)-5-{2-{2RS-hydroxy-3-(4-methyoxyphenoxy)-propylthio]ethyl}naphthalene##STR335##

Under an atmosphere of argon gas, the compound prepared in Example 10(3)(178 mg), sodium azide (30 mg) and ammonium chloride (22 mg) weresuspended in DMF (5 ml). The suspension was stirred for 20 hours at 80°C. The reaction mixture was cooled to room temperature. To the mixture,water was added. The mixture was stirred, extracted with ethyl acetatethree times. The organic layer was washed with water two times and asaturated aqueous solution of sodium chloride one time, dried over withanhydrous magnesium sulfate and concentrated. The white powder obtainedwas washed with diethylether to give the present invention compound (120mg) having the following physical data.

TLC: Rf 0.53 (MeOH: CHCl₃ : AcOH=1:18:1);

MS (FAB): m/z 467 (M+H)+;

NMR (DMSO-d6): δ 8.19 (1H, t, J=5.2 Hz), 7.69 (1H, d, J=8.4 Hz), 7.49(1H, d, J=8 Hz), 7.45 (2H, m), 7.16 (1H, d, J=7.4 Hz), 6.84 (4H, s),5.67 (2H, s), 5.22 (1H, brs), 3.92 (1H, m), 3.90 (2H, m), 3.69 (3H, s),3.30 (2H, t, J=8.2 Hz), 2.89 (2H, t, J=8.2 Hz), 2.81 (1H, dd, J=13, 5.2Hz), 2.68 (1H, dd, J=13, 6.2 Hz).

EXAMPLE 15

N-methyl-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]-methyl-1-naphthyloxy}aceticacid amide ##STR336##

To the solution of the compound prepared in Example 8(7) (325 mg) in THF(3.0 ml), aqueous 40% methylamine solution (0.6 ml) was added. Thesolution was stirred for 2.5 hours at 45° C. The reaction mixture wasdiluted with ethyl acetate, washed with 1N aqueous solution ofhydrochloric acid, water and a saturated aqueous solution of sodiumchloride, succeedingly, dried over with anhydrous magnesium sulfate andconcentrated under the reduced pressure. The residue was purified onsilica gel column chromatography (CHCl₃ : MeOH=30:1) to give the presentinvention compound (312 mg) having the following physical data.

TLC: Rf 0.64 (MeOH: CHCl₃ =1:10);

MS (FAB): m/z 536 (M+1)+, 334, 261, 228, 201;

NMR (CDCl₃): δ 8.18 (1H, m), 7.78 (1H, d, J=8.6 Hz), 7.34 (12H, m), 6.83(1H, d, J=7.7 Hz), 6.58 (1H, brs), 5.32 (1H, s), 4.70 (2H, s), 4.18 (2H,s), 3.93 (1H, m), 3.46 (2H, d, J=5.1 Hz), 2.93 (3H, d, J=5.0 Hz), 2.71(1H, dd, J=5.2, 13.8 Hz), 2.63 (1H, dd, J=1.8, 7.2 Hz), 2.56 (1H, d,J=4.0 Hz).

REFERENCE EXAMPLE 40 ##STR337##

To the solution of1-(2-hydroxy-ethyliden)-5-hydroxy-1,2,3,4-tetrahydronaphthalene (2.1 g)in ethanol (15 ml), 10% Pd-C (200 mg) was added under an atmosphere ofargon gas. The mixture was stirred vigorously under an atmosphere of H₂gas for 1 hour at room temperature. The reaction mixture was filtratedby Celite (Registered trade mark). The filtrate was concentrated underthe reduced pressure to give the title compound (1.74 g) having thefollowing physical data.

TLC: Rf 0.40 (hexane: AcOEt=2:1).

EXAMPLE 16

1-{2-[5-hydroxy-1-(1,2,3,4-tetrahydronaphthyl)]ethylthio}-3-phenoxy-2RS-propanol##STR338##

By using the compound prepared from the compound prepared in ReferenceExample 40 by the same procedure as Reference Example 12→ReferenceExample 21, and the compound prepared in Reference Example 5, thepresent invention compound having the following physical data wasobtained by the same procedure as Reference Example 24→Example 1.

TLC: Rf 0.36 (hexane: AcOEt=2:1);

NMR (CDCl₃) δ 7.30 (2H, m), 6.96 (4H, m), 6.75 (1H, d, J=7.9 Hz), 6.61(1H, d, J=7.9 Hz), 4.75 (1H, m), 4.10 (3H, m), 2.50-3.00 (7H, m),1.60-2.05 (6H, m).

EXAMPLE 17

2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydronaphthyloxy)}aceticacid methyl ester ##STR339##

By using the compound prepared in Example 16, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 2.

TLC: Rf 0.33 (acetone: benzene=1:19);

NMR (CDCl₃): δ 7.29 (2H, m), 7.00 (4H, m), 6.82 (1H, d, J=4.6 Hz), 6.52(1H, d, J=4.8), 4.63 (2H, s), 4.10 (3H, m), 3.80 (3H, s), 2.55-2.97 (8H,m), 1.60-2.10 (6H, m).

EXAMPLE 18

2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydronaphthyloxy)}aceticacid ##STR340##

By using the compound prepared in Example 17, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 3.

TLC: Rf 0.5 (MeOH CHCl₃ : AcOH=10:100 1);

MS (APCl): m/z 415 (M-1)+, 357, 263, 93;

NMR (CDCl₃): δ 7.30 (2H, m), 6.82-7.13 (5H, m), 6.55 (1H, d, J=8.0 Hz),4.66 (2H, s), 4.09 (3H, m), 2.50-2.98 (7H, m), 1.60-2.10 (6H, m).

EXAMPLE 19

1-cyanomethoxy-5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-5,6,7,8-tetrahydronaphthalene##STR341##

By using the compound prepared in Example 16, the present inventioncompound having the following physical data was obtained by the sameprocedure as Example 10.

TLC: Rf 0.33 (acetone: benzene=1:19);

MS (El): m/z 397 (M)+, 304, 286, 245, 213, 184, 173, 157, 145;

NMR (CDCl₃): δ 7.30 (2H, m), 7.13 (1H, dd, J=8.0, 8.0 Hz), 6.95 (4H, m),6.71 (1H, d, J=8.0 Hz), 4.76 (2H, s), 4.10 (3H, m), 2.50-3.00 (8H, m),1.54-2.08 (6H, m).

FORMULATION EXAMPLE 1

The following compounds were admixed in conventional method and punchedout to obtain 100 tablets each containing 5 mg of active ingredient.

    ______________________________________                                        • 2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}            acetic acid..............................................                                                500 mg                                           • Carboxymethylcellulose calcium................... 200 mg                                            • Magnesium stearate................                                   ............... 100 mg                           • Micro crystalline cellulose...................... 9.2 g             ______________________________________                                    

What we claim is:
 1. A naphthyloxyacetic acid derivative of the generalformula (I) ##STR342## wherein A is --(C1-4 alkylene)--COOR¹ in which R¹is hydrogen or C1-4 alkyl;E is (i) single bond or (ii) C1-6 alkylene; Gis --S--, --SO--, or --SO₂ --; L is (i) C1-6 alkylene, (ii) --(CH₂)_(m)--CH═CH--(CH₂)_(n) -- in which m is 0 or an integer of 1-3, n is 0 or aninteger of 1-3 or (iii) --(CH₂)_(x) --CH(OH)--(CH₂)_(y) -- in which x isan integer of 1-3, y is 0 or an integer of 1-3; ##STR343## in which eachphenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy,halogen, nitro or trifluoromethyl; in the formula ##STR344## with theproviso that, (1) when G is --SO-- or --SO₂ --, M is neither ##STR345##in which each phenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4alkoxy, halogen, nitro or trifluoromethyl, (2) when m in L is 0, G is--SO-- or --SO₂ --, (3) when n in L is 0, M is ##STR346## in which eachphenyl group may be substituted by 1-3 of C1-4 alkyl, C1-4 alkoxy,halogen, nitro or trifluoro methyl, and (4) when y in L is 0, M is##STR347## in which each phenyl group may be substituted by 1-3 of C1-4alkyl, C1-4 alkoxy, halogen, nitro or trifluoromethyl, or non-toxic saltthereof, non-toxic acid addition salt thereof or their hydrate.
 2. Acompound according to claim 1, wherein L is --(CH₂)_(m)--CH═CH--(CH₂)_(n) -- or --(CH₂)_(x) --CH(OH)--(CH₂)_(y) --.
 3. Apharmaceutical composition which comprises a carrier and an effectiveamount of naphthyloxyacetic acid derivative of the formula (1) depictedin claim 1, non-toxic salt thereof, non-toxic acid addition salt thereofor their hydrate.
 4. A prostaglandin E₂ antagonist or agonist whichcomprises a naphthyloxyacetic acid derivative of the formula (I)depicted in claim 1, non-toxic salt thereof, non-toxic acid additionsalt thereof or their hydrate.
 5. A compound according to claim 2, whichis(1)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid methyl ester, (2)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}aceticacid methyl ester, (3)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}-aceticacid methyl ester, (4)2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acidmethyl ester, (5)2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}acetic acidmethyl ester, (6)2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]acetic acidmethyl ester, (7)2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]aceticacid methyl ester, (8)2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]aceticacid methyl ester, (9)2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}acetic acidmethyl ester, (10)2-{5-[3-(2RS-hydroxy-2-phenylethylsulfinyl)propyl]-1-naphthyloxy}aceticacid methyl ester, (11)2-{5-[3-(2RS-hydroxy-2-phenylethylsulfonyl)propyl]-1-naphthyloxy}aceticacid methyl ester, (12)2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]acetic acid methylester, (13)2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acidmethyl ester, (14)2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]acetic acidmethyl ester, (15) 2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]aceticacid methyl ester, (16)2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid methyl ester,(17)2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester, (18)2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester, (19)2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester, (20)2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid methyl ester, (21)2-{5-[2-(2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio)-ethyl]-1-naphthyloxy}aceticacid methyl ester, (22)2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}aceticacid methyl ester, (23)2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]-aceticacid methyl ester, (24)2-{5-[2RS-hydroxy-3-(1-phenyl-1-(4-chlorophenyl)methoxy)propylthio]-methyl-1-naphthyloxy}aceticacid methyl ester, (25)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid, (26)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfinyl)ethyl]-1-naphthyloxy}aceticacid, (27)2-{5-[2-(2RS-hydroxy-3-phenoxypropylsulfonyl)ethyl]-1-naphthyloxy}-aceticacid, (28)2-{5-[2-(2R-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid, (29)2-{5-[2-(2S-hydroxy-3-phenoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid, (30)2-[5-(2RS-hydroxy-3-phenoxypropylthio)methyl-1-naphthyloxy]-acetic acid,(31)2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)methyl-1-naphthyloxy]aceticacid, (32)2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)methyl-1-naphthyloxy]aceticacid, (33)2-{5-[3-(2RS-hydroxy-2-phenylethylthio)propyl]-1-naphthyloxy}aceticacid, (34) 2-[5-(2RS-hydroxy-3-phenoxypropylthio)-1-naphthyloxy]aceticacid, (35)2-[5-(2RS-hydroxy-3-phenoxypropylsulfinyl)-1-naphthyloxy]acetic acid,(36) 2-[5-(2RS-hydroxy-3-phenoxypropylsulfonyl)-1-naphthyloxy]aceticacid, (37) 2-[5-(3-styrylsulfinylpropyl)-1-naphthyloxy]acetic acid, (38)2-[5-(3-styrylsulfonylpropyl)-1-naphthyloxy]acetic acid, (39)2-{5-[2-(2RS-hydroxy-3-(4-chlorophenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid, (40)2-{5-[2-(2RS-hydroxy-3-(4-methylphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid, (41)2-{5-[2-(2RS-hydroxy-3-(4-methoxyphenoxy)propylthio)ethyl]-1-naphthyloxy}aceticacid, (42)2-{5-[2-(2RS-hydroxy-3-diphenylmethoxypropylthio)ethyl]-1-naphthyloxy}-aceticacid, (43)2-{5-[2-(2RS-hydroxy-3-phenylthiopropylthio)ethyl]-1-naphthyloxy}aceticacid, (44)2-[5-(2RS-hydroxy-3-diphenylmethoxypropylthio)methyl-1-naphthyloxy]aceticacid, (45)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydro-naphthyloxy)}aceticacid methyl ester, or (46)2-{5-[2-(2RS-hydroxy-3-phenoxypropylthio)ethyl]-1-(5,6,7,8-tetrahydro-naphthyloxy)}aceticacid.